Yosuke Shikama, Naozumi Ishimaru, Yasusei Kudo, Rieko Arakaki, Yukiko Bandou, Nanako Aki and Makoto Funaki : High Levels of Saturated Fatty Acids may Exacerbate the Pathogenesis of Primary Sjögrens Syndrome, Springer, Dec. 2014.
Academic Paper (Judged Full Paper):
1.
Motoharu Sarubo, Yasuhiro Mouri, Akira Moromizato, Azusa Yamada, Shengjan Jin, Wenhua Shao, Hiroko Hagita, Keiko Miyoshi and Yasusei Kudo : Involvement of TGFBI-TAGLN axis in cancer stem cell property of head and neck squamous cell carcinoma., Scientific Reports, Vol.14, No.1, 6767, 2024.
(Summary)
Head and neck squamous cell carcinoma (HNSCC) is a significant healthcare burden globally. Previous research using single-cell transcriptome analysis identified TGFBI as a crucial marker for the partial-epithelial-mesenchymal transition (partial-EMT) program. However, the precise role of TGFBI in HNSCC progression remains unclear. Therefore, our study aimed to clarify the impact of TGFBI on the malignant behavior of HNSCC cells. Through RNA-sequencing data from the TCGA database, we validated that increased TGFBI expression correlates with a higher occurrence of lymph node metastasis and unfavorable prognosis in HNSCC cases. Functional experiments demonstrated that TGFBI overexpression enhances the ability of sphere formation, indicating stem-cell-like properties. Conversely, TGFBI depletion reduces sphere formation and suppresses the expression of cancer stem cell (CSC) markers. RNA-sequencing analysis of TGFBI-overexpressing and control HNSCC cells revealed TAGLN as a downstream effector mediating TGFBI-induced sphere formation. Remarkably, TAGLN depletion abolished TGFBI-induced sphere formation, while its overexpression rescued the suppressed sphere formation caused by TGFBI depletion. Moreover, elevated TAGLN expression showed correlations with the expression of TGFBI and partial-EMT-related genes in HNSCC cases. In conclusion, our findings suggest that TGFBI may promote CSC properties through the upregulation of TAGLN. These novel insights shed light on the involvement of the TGFBI-TAGLN axis in HNSCC progression and hold implications for the development of targeted therapies.
(Keyword)
Humans / Squamous Cell Carcinoma of Head and Neck / Carcinoma, Squamous Cell / Head and Neck Neoplasms / Cell Line, Tumor / Neoplastic Stem Cells / Epithelial-Mesenchymal Transition / RNA / Gene Expression Regulation, Neoplastic
Integrins in HGECs are regulated by periostin secreted from HPL cells and MSCs. This result suggests that periostin maintains gingival cell adhesion and regulates bacterial invasion/infection. Therefore, the functional regulation of periostin-secreting cells is important in preventing periodontitis.
Shengjian Jin, Takaaki Tsunematsu, Taigo Horiguchi, Yasuhiro Mouri, Wenhua Shao, Keiko Miyoshi, Hiroko Hagita, Motoharu Sarubo, Natsumi Fujiwara, Qi Guangying, Naozumi Ishimaru and Yasusei Kudo : Involvement of the OTUB1-YAP1 axis in driving malignant behaviors of head and neck squamous cell carcinoma., Cancer Medicine, Vol.12, No.24, 22156-22169, 2023.
(Summary)
This study highlights the critical role of OTUB1 in HNSCC progression via modulating YAP1. Targeting the OTUB1-YAP1 axis holds promise as a potential therapeutic strategy for HNSCC treatment.
(Keyword)
deubiquitinating enzyme (DUB) / head and neck squamous cell carcinoma / invasion / OTUB1 / YAP
Kayo Yoshida, Kaya Yoshida, Mariko Seyama, Yuka Hiroshima, Mana Mekata, Natsumi Fujiwara, Yasusei Kudo and Kazumi Ozaki : Porphyromonas gingivalis outer membrane vesicles in cerebral ventricles activate microglia in mice, Oral Diseases, Vol.29, No.8, 3688-3697, 2023.
(Summary)
Objective: Porphyromonas gingivalis (Pg) is thought to be involved in the progression of Alzheimer's disease (AD). Whether Pg or its contents can reach the brain and directly affect neuropathology is, however, unknown. Here, we investigated whether outer membrane vesicles (OMVs) of Pg translocate to the brain and induce the pathogenic features of AD. Material and Methods: Pg OMVs were injected into the abdominal cavity of mice for 12 weeks. Pg OMV translocation to the brain was detected by immunohistochemistry using an anti-gingipain antibody. Tau protein and microglial activation in the mouse brain were examined by western blotting and immunohistochemistry. The effect of gingipains on inflammation was assessed by real-time polymerase chain reaction using human microglial HMC3 cells. Results: Gingipains were detected in the region around cerebral ventricles, choroid plexus, and ventricular ependymal cells in Pg OMV-administered mice. Tau and phosphorylated Tau protein increased and microglia were activated. Pg OMVs also increased the gene expression of proinflammatory cytokines in HMC3 cells in a gingipain-dependent manner. Conclusion: Pg OMVs, including gingipains, can reach the cerebral ventricle and induce neuroinflammation by activating microglia. Pg OMVs may provide a better understanding of the implications of periodontal diseases in neurodegenerative conditions such as AD.
Biopsy is a commonly used method for determining pathological diagnoses by directly using human tissues and cells. Biopsies are widely used to determine disease progression and treatment efficacy. Although organs and tissues are usually obtained by sacrifice during animal experiments, it is theoretically possible to use the same biopsy techniques in humans. In the present study, we examined the feasibility of performing four repeated liver biopsies in a spontaneous metabolic syndrome mouse model. Even though a small number of mice died accidently, most mice were able to undergo four liver biopsies without significant adverse events. We also performed three liver biopsies in mouse liver tumor carcinogen models at 4, 8, and 12 weeks of age. In addition to the sample collected at 16 weeks of age during sacrifice, we successfully collected four liver samples from the same mice at different stages of disease progression. The application of this liver biopsy technique might make it possible for direct evaluation of pathological conditions in the same individual over time, thereby reducing the number of experimental animals.
Anrizandy Narwidina, Aya Miyazaki, Kokoro Iwata, Rika Kurogoushi, Asuna Sugimoto, Yasusei Kudo, Keita Kawarabayashi, Yoshihito Yamakawa, Yuki Akazawa, Takamasa Kitamura, Hiroshi Nakagawa, Kimiko Ueda Yamaguchi, Tomokazu Hasegawa, Keigo Yoshizaki, Satoshi Fukumoto, Akihito Yamamoto, Naozumi Ishimaru, Tomonori Iwasaki and Tsutomu Iwamoto : Iroquois homeobox 3 regulates odontoblast proliferation and differentiation mediated by Wnt5a expression., Biochemical and Biophysical Research Communications, Vol.650, 47-54, 2023.
(Summary)
Iroquois homeobox (Irx) genes are TALE-class homeobox genes that are evolutionarily conserved across species and have multiple critical cellular functions in fundamental tissue development processes. Previous studies have shown that Irxs genes are expressed during tooth development. However, the precise roles of genes in teeth remain unclear. Here, we demonstrated for the first time that Irx3 is an essential molecule for the proliferation and differentiation of odontoblasts. Using cDNA synthesized from postnatal day 1 (P1) tooth germs, we examined the expression of all Irx genes (Irx1-Irx6) by RT-PCR and found that all genes except Irx4 were expressed in the tooth tissue. Irx1-Irx3 a were expressed in the dental epithelial cell line M3H1 cells, while Irx3 and Irx5 were expressed in the dental mesenchymal cell line mDP cells. Only Irx3 was expressed in both undifferentiated cell lines. Immunostaining also revealed the presence of IRX3 in the dental epithelial cells and mesenchymal condensation. Inhibition of endogenous Irx3 by siRNA blocks the proliferation and differentiation of mDP cells. Wnt3a, Wnt5a, and Bmp4 are factors involved in odontoblast differentiation and were highly expressed in mDP cells by quantitative PCR analysis. Interestingly, the expression of Wnt5a (but not Wnt3a or Bmp4) was suppressed by Irx3 siRNA. These results suggest that Irx3 plays an essential role in part through the regulation of Wnt5a expression during odontoblast proliferation and differentiation.
Wenhua Shao, Takaaki Tsunematsu, Masaaki Umeda, Hiroaki Tawara, Natsumi Fujiwara, Yasuhiro Mouri, Rieko Arakaki, Naozumi Ishimaru and Yasusei Kudo : Cancer cell-derived novel periostin isoform promotes invasion in head and neck squamous cell carcinoma., Cancer Medicine, Vol.12, No.7, 8510-8525, 2023.
(Summary)
It recently has been reported that partial-epithelial-mesenchymal transition (p-EMT) program is associated with metastasis in head and neck squamous cell carcinoma (HNSCC). We previously have identified POSTN (which encodes periostin) as an invasion-promoting molecule in HNSCC. Interestingly, POSTN expression is frequently observed in cancer cells with higher p-EMT score by using a previous single-cell transcriptomic data of HNSCC cases. Although it is known that POSTN has 11 splicing variants, the role of them has not been determined in HNSCC. Here, we found that HNSCC cells with EMT features expressed POSTN isoforms, Iso3 (lacking exon 17 and 21) and Iso5 (lacking exon 17), whereas fibroblast expressed Iso3 and Iso4 (lacking exon 17, 18, and 21). The expression of POSTN Iso3 and Iso4 are known to be widely observed in various cell types including stromal cells. Therefore, we focused on the role of novel cancer cell-derived POSTN isoform, Iso5, in HNSCC. Single overexpression of POSTN Iso5 as well as Iso3 promoted invasion. Surprisingly, Iso5 synergistically promoted invasion together with Iso3. Notably, Iso5 as well as Iso3 upregulated p-EMT-related genes. We suggest that a novel cancer-specific POSTN isoform lacking exon 17 (Iso5) can be a useful marker for detecting cancer cells undergoing p-EMT. Moreover, a POSTN Iso5 can be a novel target for diagnosis and therapy in HNSCC.
Jin Shengjian, Yasusei Kudo and Taigo Horiguchi : The Role of Deubiquitinating Enzyme in Head and Neck Squamous Cell Carcinoma, International Journal of Molecular Sciences, Vol.24, 552, 2022.
(Summary)
Ubiquitination and deubiquitination are two popular ways for the post-translational modification of proteins. These two modifications affect intracellular localization, stability, and function of target proteins. The process of deubiquitination is involved in histone modification, cell cycle regulation, cell differentiation, apoptosis, endocytosis, autophagy, and DNA repair after damage. Moreover, it is involved in the processes of carcinogenesis and cancer development. In this review, we discuss these issues in understanding deubiquitinating enzyme (DUB) function in head and neck squamous cell carcinoma (HNSCC), and their potential therapeutic strategies for HNSCC patients are also discussed.
(Keyword)
head and neck squamous cell carcinoma / deubiquitination / ubiquitination
Wenhua Shao, Orgil Jargalsaikhan, Mayuko Shimizu, Qinyi Cai, Hirohisa Ogawa, Yuko Miyakami, Kengo Atsumi, Mitsuru Tomita, Mitsuko Sutoh, Shunji Toyohara, Ryoji Hokao, Yasusei Kudo, Takeshi Oya and Koichi Tsuneyama : Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice., International Journal of Molecular Sciences, Vol.23, No.19, 2022.
(Summary)
Male Tsumura-Suzuki Obese Diabetes (TSOD) mice, a spontaneous metabolic syndrome model, develop non-alcoholic steatohepatitis and liver tumors by feeding on a standard mouse diet. Nearly 70% of liver tumors express glutamine synthetase (GS), a marker of hepatocellular carcinoma. In contrast, approximately 30% are GS-negative without prominent nuclear or structural atypia. In this study, we examined the characteristics of the GS-negative tumors of TSOD mice. Twenty male TSOD mice were sacrificed at 40 weeks and a total of 21 tumors were analyzed by HE staining and immunostaining of GS, liver fatty acid-binding protein (L-FABP), serum amyloid A (SAA), and beta-catenin. With immunostaining for GS, six (29%) tumors were negative. Based on the histological and immunohistological characteristics, six GS-negative tumors were classified into several subtypes of human hepatocellular adenoma (HCA). One large tumor showed generally similar findings to inflammatory HCA, but contained small atypical foci with GS staining and partial nuclear beta-catenin expression suggesting malignant transformation. GS-negative tumors of TSOD mice contained features similar to various subtypes of HCA. Different HCA subtypes occurring in the same liver have been reported in humans; however, the diversity of patient backgrounds limits the ability to conduct a detailed, multifaceted analysis. TSOD mice may share similar mechanisms of HCA development as in humans. It is timely to review the pathogenesis of HCA from both genetic and environmental perspectives, and it is expected that TSOD mice will make further contributions in this regard.
Yoshiko Yamamura, Keiko Miyoshi, Yasuhiro Mouri, Yasusei Kudo and Youji Miyamoto : miR 155 5p can be involved in acquisition of osseointegration on titanium surface, In Vitro Cellular & Developmental Biology. Animal, Vol.58, No.8, 693-701, 2022.
(Summary)
Dental implants made of titanium are commonly used. Although titanium implants succeed by osseointegration with bone, the detailed molecular mechanism of osseointegration is unclear. To clarify the involvement of microRNA (miRNA) in the acquisition of osseointegration on titanium, here we compared the miRNA expression profiles of mouse osteoblast-like cells (MC3T3-E1) cultured on titanium-, gold-, and stainless steel-coating glass dishes by microarray analysis. Three kinds of metals, namely titanium, gold, and stainless steel, were coated on the surface of the glass dishes by sputtering with similar roughness and shape of their surface. After MC3T3-E1 cells were cultured on the dishes without coating or coating with titanium, gold, or stainless steel for 6 h, total RNA was extracted, and miRNA expression was analyzed by microarray. To confirm the expression of the selected miRNA during osteogenic differentiation of MC3T3-E1 cells, real-time PCR analysis was performed. Furthermore, the effects of selected miRNA were examined by ectopic overexpression in MC3T3-E1 cells. The microarray analysis revealed that the expressions of miR-155-5p and miR-7023-3p were significantly increased in MC3T3-E1 cells cultured on titanium-coating glass dishes, compared to non-coating, gold-, and stainless steel-coating glass dishes. Interestingly, miR-155-5p was upregulated during osteogenic differentiation of MC3T3-E1 cells. Furthermore, overexpression of miR-155-5p enhanced the expression of Runx2 and Col1a1. In this study, miR-155-5p may be involved in the acquisition of osseointegration on titanium implant via upregulating osteogenic differentiation-related genes.
Monal Yuwanati, Ramya Ramadoss, Yasusei Kudo, Pratibha Ramani and Mullainathan Murugan Senthil : Prevalence of oral submucous fibrosis among areca nut chewers: A systematic review and meta-analysis., Oral Diseases, 2022.
(Summary)
Available evidence suggested a low prevalence of OSMF in ANC, although further large-scale studies are recommended to validate this finding. Understanding the prevalence and distribution patterns of OSMF might aid intervention healthcare programs and contribute to the reduction of the oral cancer burden related to OSMF.
Takaharu Kudoh, Akihiro Haga, Keiko Kudoh, Akira Takahashi, Motoharu Sasaki, Yasusei Kudo, Hitoshi Ikushima and Youji Miyamoto : Radiomics analysis of [18F]-fluoro-2-deoxyglucose positron emission tomography for the prediction of cervical lymph node metastasis in tongue squamous cell carcinoma, Oral Radiology, 2022.
(Summary)
This study aimed to create a predictive model for cervical lymph node metastasis (CLNM) in patients with tongue squamous cell carcinoma (SCC) based on radiomics features detected by [F]-fluoro-2-deoxyglucose (F-FDG) positron emission tomography (PET). A total of 40 patients with tongue SCC who underwent F-FDG PET imaging during their first medical examination were enrolled. During the follow-up period (mean 28 months), 20 patients had CLNM, including six with late CLNM, whereas the remaining 20 patients did not have CLNM. Radiomics features were extracted from F-FDG PET images of all patients irrespective of metal artifact, and clinicopathological factors were obtained from the medical records. Late CLNM was defined as the CLNM that occurred after major treatment. The least absolute shrinkage and selection operator (LASSO) model was used for radiomics feature selection and sequential data fitting. The receiver operating characteristic curve analysis was used to assess the predictive performance of the F-FDG PET-based model and clinicopathological factors model (CFM) for CLNM. Six radiomics features were selected from LASSO analysis. The average values of the area under the curve (AUC), accuracy, sensitivity, and specificity of radiomics analysis for predicting CLNM from F-FDG PET images were 0.79, 0.68, 0.65, and 0.70, respectively. In contrast, those of the CFM were 0.54, 0.60, 0.60, and 0.60, respectively. The F-FDG PET-based model showed significantly higher AUC than that of the CFM. The F-FDG PET-based model has better potential for diagnosing CLNM and predicting late CLNM in patients with tongue SCC than the CFM.
Satoru Kisoda, Yasuhiro Mouri, Naoya Kitamura, Tetsuya Yamamoto, Keiko Miyoshi and Yasusei Kudo : The role of partial-EMT in the progression of head and neck squamous cell carcinoma., Journal of Oral Biosciences, Vol.64, No.2, 176-182, 2022.
(Summary)
In this review, we highlight the features of partial-EMT in HNSCC by summarizing previous studies. Moreover, we discuss the therapeutic potential for targeting partial-EMT.
(Keyword)
Carcinoma, Squamous Cell / Epithelial-Mesenchymal Transition / Head and Neck Neoplasms / Humans / Lymphatic Metastasis / Squamous Cell Carcinoma of Head and Neck
Yosuke Shikama, Mie Kurosawa, Masae Furukawa, Yasusei Kudo, Naozumi Ishimaru and Kenji Matsushita : The Priming Potential of Interferon Lambda-1 for Antiviral Defense in the Oral Mucosa., Inflammation, Vol.45, No.3, 1348-1361, 2022.
(Summary)
The oral mucosa is one of the first lines of the innate host defense system against microbial invasion. Interferon (IFN) lambda-1 (IFN-λ1), a type III IFN, exhibits type I IFN-like antiviral activity. In contrast to ubiquitously expressed type I IFN receptors, IFN-λ receptor 1 (IFN-λR1), which has higher affinity for type III IFNs than low-affinity interleukin (IL)-10 receptor 2, is mainly expressed on epithelial cells. Although IFN-λ1 has been shown to exert antiviral effects in the respiratory tract, gastrointestinal tract, and skin, the regulation of type III IFN receptor expression and its functions in the oral mucosa remain unclear. We herein showed the expression of IFN-λR1 in human gingival keratinocytes. The expression of IL-6, angiotensin-converting enzyme 2 (a critical molecule for severe acute respiratory syndrome coronavirus 2 infection), and IL-8 in human primary gingival keratinocytes (HGK) were significantly higher following treatments with either type I IFN (IFN-β) or type II IFN (IFN-γ) than with IFN-λ1. However, the IFN-λ1 treatment strongly induced toll-like receptor (TLR) 3 and retinoic acid-inducible gene I (RIG-I), which mainly recognize viral nucleic acids, via the STAT1-mediated pathway. Furthermore, a stimulation with a RIG-I or TLR3 agonist promoted the production of IL-6, IL-8, and IFN-λ in HGK, which was significantly enhanced by a pretreatment with IFN-λ1. These results suggest that IFN-λ1 may contribute to the activation of innate immune responses to oral viral infections by up-regulating the expression of RIG-I and TLR3 and priming their functions in keratinocytes.
Kokoro Iwata, Keita Kawarabayashi, Keigo Yoshizaki, Tian Tian, Kan Saito, Asuna Sugimoto, Rika Kurogoushi, Aya Yamada, Akihito Yamamoto, Yasusei Kudo, Naozumi Ishimaru, Satoshi Fukumoto and Tsutomu Iwamoto : von Willebrand factor D and EGF domains regulate ameloblast differentiation and enamel formation., Journal of Cellular Physiology, Vol.237, No.3, 1964-1979, 2021.
(Summary)
Cell- and tissue-specific extracellular matrix (ECM) composition plays an important role in organ development, including teeth, by regulating cell behaviors, such as cell proliferation and differentiation. Here, we demonstrate for the first time that von Willebrand factor D and epidermal growth factor (EGF) domains (Vwde), a previously uncharacterized ECM protein, is specifically expressed in teeth and regulates cell proliferation and differentiation in inner enamel epithelial cells (IEEs) and enamel formation. We identified the Vwde as a novel ECM protein through bioinformatics using the NCBI expressed sequence tag database for mice. Vwde complementary DNA encodes 1773 amino acids containing a signal peptide, a von Willebrand factor type D domain, and tandem calcium-binding EGF-like domains. Real-time polymerase chain reaction demonstrated that Vwde is highly expressed in tooth tissue but not in other tissues including the brain, lung, heart, liver, kidney, and bone. In situ hybridization revealed that the IEEs expressed Vwde messenger RNA in developing teeth. Immunostaining showed that VWDE was localized at the proximal and the distal ends of the pericellular regions of the IEEs. Vwde was induced during the differentiation of mouse dental epithelium-derived M3H1 cells. Vwde-transfected M3H1 cells secreted VWDE protein into the culture medium and inhibited cell proliferation, whereas ameloblastic differentiation was promoted. Furthermore, Vwde increased the phosphorylation of extracellular signal-regulated kinase 1/2 and protein kinase B and strongly induced the expression of the intercellular junction protein, N-cadherin (Ncad). Interestingly, the suppression of endogenous Vwde inhibited the expression of Ncad. Finally, we created Vwde-knockout mice using the CRISPR-Cas9 system. Vwde-null mice showed low mineral density, rough surface, and cracks in the enamel, indicating the enamel hypoplasia phenotype. Our findings suggest that Vwde assembling the matrix underneath the IEEs is essential for Ncad expression and enamel formation.
Shu Chen, Naofumi Tamaki, Yasusei Kudo, Takaaki Tsunematsu, Kaname Miki, Naozumi Ishimaru and Hiro-O Ito : Protective effects of resveratrol against 5-fluorouracil-induced oxidative stress and inflammatory responses in human keratinocytes., Journal of Clinical Biochemistry and Nutrition, Vol.69, No.3, 238-246, 2021.
(Summary)
-acetylcysteine reduced ROS levels without affecting the expression of pro-inflammatory cytokines. Resveratrol might be useful for preventing 5-FU-induced adverse effects by activating anti-oxidant and anti-inflammatory responses.
Kazumi Takaishi, Yasusei Kudo, Shinji Kawahito and Hiroshi Kitahata : Clinically relevant concentration of propofol and benzodiazepines did not affect in vitro angiogenesis., Journal of Anesthesia, Vol.35, No.6, 870-878, 2021.
(Summary)
Angiogenesis, one of regenerative medicine, is essential in the process of wound healing. The detailed effects of intravenous anesthetics and sedatives used during perioperative period have not yet been clarified. We investigated the effects of benzodiazepines and propofol on in vitro capillary tube formation. The effects of midazolam, diazepam and propofol (1, 10, 50 M each) on proliferation of human umbilical vein endothelial cells (HUVEC) and normal human diploid fibroblasts (NHDF) were determined. Quantitation of migration was achieved by measuring the fluorescence of migrating HUVEC using angiogenesis system. The effects of midazolam, diazepam and propofol on in vitro angiogenesis were investigated in co-cultured HUVEC and NHDF incubated. The effects of midazolam on activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases were examined by Western blot analysis using phospho-specific antibodies. Parametric data were analyzed with one-way repeated measures analysis of variance followed by the Scheff test. A value of P < 0.05 was considered statistically significant. Fifty M of midazolam significantly impaired endothelial cell proliferation, migration, and in vitro capillary tube formation. Propofol, diazepam or lower dose midazolam did not show any enhancing or suppressive effects on in vitro angiogenesis. Fifty M of midazolam remarkably activated ERK, but not p38 MAPK in HUVEC. Propofol and benzodiazepines except high-dose midazolam did not affect in vitro angiogenesis. High-dose midazolam may impair in vitro capillary tube formation due to by suppressing proliferation and migration of endothelial cells via activation of ERK.
Wenhua Shao, Natsumi Fujiwara, Yasuhiro Mouri, Satoru Kisoda, Kayo Yoshida, Kaya Yoshida, Hiromichi Yumoto, Kazumi Ozaki, Naozumi Ishimaru and Yasusei Kudo : Conversion from epithelial to partial-EMT phenotype by Fusobacterium nucleatum infection promotes invasion of oral cancer cells., Scientific Reports, Vol.11, No.1, 14943, 2021.
(Summary)
The ability of cancer cells to undergo partial-epithelial mesenchymal transition (p-EMT), rather than complete EMT, poses a higher metastatic risk. Although Fusobacterium nucleatum mainly inhabits in oral cavity, attention has been focused on the F. nucleatum involvement in colorectal cancer development. Here we examined the p-EMT regulation by F. nucleatum in oral squamous cell carcinoma (OSCC) cells. We cultured OSCC cells with epithelial, p-EMT or EMT phenotype with live or heat-inactivated F. nucleatum. Expression of the genes involved in epithelial differentiation, p-EMT and EMT were examined in OSCC cells after co-culture with F. nucleatum by qPCR. Cell growth and invasion of OSCC cells were also examined. Both live and heat-inactivated F. nucleatum upregulated the expression of p-EMT-related genes in OSCC cells with epithelial phenotype, but not with p-EMT or EMT phenotype. Moreover, F. nucleatum promoted invasion of OSCC cells with epithelial phenotype. Co-culture with other strains of bacteria other than Porphyromonas gingivalis did not alter p-EMT-related genes in OSCC cells with epithelial phenotype. F. nucleatum infection may convert epithelial to p-EMT phenotype via altering gene expression in OSCC. Oral hygiene managements against F. nucleatum infection may contribute to reduce the risk for an increase in metastatic ability of OSCC.
Go Ohe, Yasusei Kudo, Kumiko Kamada, Yasuhiro Mouri, Natsumi Takamaru, Keiko Kudoh, Naito Kurio and Youji Miyamoto : Soluble Factor from Oral Cancer Cell Lines Inhibits Interferon-γ Production by OK-432 via CD40/CD40Ligand Pathway, Cancers, Vol.13, No.13, 2021.
Natsuko Hichijo, Yasusei Kudo and Eiji Tanaka : Orthodontic treatment of open bite involved in diffuse hypercementosis: A case report., The Journal of the American Dental Association, Vol.152, No.2, 166-175, 2021.
(Summary)
Open bite is considered one of the most complicated malocclusions in orthodontic treatment. In this study, the authors successfully treated total open bite involved in hypercementosis using orthodontic miniscrews. A woman aged 25 years 8 months had total open bite. Her occlusal contact at the maximum intercuspation was present at the right second molars. A panoramic radiograph showed diffuse hypercementosis. The titanium miniscrews were interradicullay implanted between the first and second molars, and intrusion force was applied for 14 months. After active treatment, the patient's maxillary first molars showed about 1.6-millimeters of intrusion, resulting in counterclockwise mandibular rotation. Her acceptable occlusion was maintained after 1.0-year retention. Miniscrews might be useful tool to improve malocclusion involved in diffuse hypercementosis though they are considered to be difficult to move and brought on ankylosis.
(Keyword)
Adult / Cephalometry / Female / Humans / Hypercementosis / Malocclusion, Angle Class II / Open Bite / Orthodontic Anchorage Procedures / Tooth Movement Techniques
Yoshiko Yamamura, Yasusei Kudo, Keiko Kudoh and Youji Miyamoto : Actinomycotic osteomyelitis of the mandible with bone destruction: Two case reports with a review of the Japanese literatures, Oral Science International, 2021.
Naoya Kitamura, Shinya Sento, Yasumasa Yoshizawa, Eri Sasabe, Yasusei Kudo and Tetsuya Yamamoto : Current Trends and Future Prospects of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma., International Journal of Molecular Sciences, Vol.22, No.1, 240, 2020.
(Summary)
In recent years, advances in drug therapy for head and neck squamous cell carcinoma (HNSCC) have progressed rapidly. In addition to cytotoxic anti-cancer agents such as platinum-based drug (cisplatin and carboplatin) and taxane-based drugs (docetaxel and paclitaxel), epidermal growth factor receptor-tyrosine kinase inhibitors (cetuximab) and immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) antibodies (nivolumab and pembrolizumab) have come to be used. The importance of anti-cancer drug therapy is increasing year by year. Therefore, we summarize clinical trials of molecular targeted therapy and biomarkers in HNSCC from previous studies. Here we show the current trends and future prospects of molecular targeted therapy in HNSCC.
Takaaki Tsunematsu, Rieko Arakaki, Hidehiko Kawai, Jan Ruppert, Koichi Tsuneyama, Naozumi Ishimaru, C William Earnshaw, Michele Pagano and Yasusei Kudo : is required for the termination of chromosomal passenger complex activity upon mitotic exit., Journal of Cell Science, Vol.133, No.18, 2020.
(Summary)
terminates CPC activity upon mitotic exit and thereby contributes to proper control of DNA replication.
Natsumi Fujiwara, Naoya Kitamura, Kaya Yoshida, Tetsuya Yamamoto, Kazumi Ozaki and Yasusei Kudo : Involvement of Fusobacterium Species in Oral Cancer Progression: A Literature Review Including Other Types of Cancer, International Journal of Molecular Sciences, Vol.21, No.17, 6207, 2020.
(Summary)
Chronic inflammation caused by infections has been suggested to be one of the most important cause of cancers. It has recently been shown that there is correlation between intestinal bacteria and cancer development including metastasis. As over 700 bacterial species exist in an oral cavity, it has been concerning that bacterial infection may cause oral cancer. However, the role of bacteria regarding tumorigenesis of oral cancer remains unclear. Several papers have shown that species deriving the oral cavities, especially, play a crucial role for the development of colorectal and esophageal cancer. is a well-known oral bacterium involved in formation of typical dental plaque on human teeth and causing periodontal diseases. The greatest characteristic of is its ability to adhere to various bacteria and host cells. Interestingly, is frequently detected in oral cancer tissues. Moreover, detection of is correlated with the clinical stage of oral cancer. Although the detailed mechanism is still unclear, species have been suggested to be associated with cell adhesion, tumorigenesis, epithelial-to-mesenchymal transition, inflammasomes, cell cycle, etc. in oral cancer. In this review, we introduce the reports focused on the association of species with cancer development and progression including oral, esophageal, and colon cancers.
Riki Tomita, Naoya Kitamura, Yasumasa Yoshizawa, Eri Sasabe, Yasusei Kudo and Tetsuya Yamamoto : A case of large varix including partially organizing thrombosis on the oral floor, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, Vol.32, No.4, 313-315, 2020.
Shinya Sento, Yasusei Kudo, Kenji Hibiya, Naozumi Ishimaru, Eri Sasabe, Naoya Kitamura and Tetsuya Yamamoto : Hyalinizing clear cell carcinoma of the anterior lingual salivary gland: A case report and review of the literature, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, Vol.32, No.4, 267-274, 2020.
Satoru Kisoda, Wenhua Shao, Natsumi Fujiwara, Yasuhiro Mouri, Takaaki Tsunematsu, Shengjian Jin, Rieko Arakaki, Naozumi Ishimaru and Yasusei Kudo : Prognostic value of partial EMT-related genes in head and neck squamous cell carcinoma by a bioinformatic analysis., Oral Diseases, Vol.26, No.6, 1149-1156, 2020.
(Summary)
Our findings suggest that p-EMT program may be involved in poor prognosis of HNSCC. SERPINE1, ITGA5, TGFBI, P4HA2, CDH13, and LAMC2 can be used for a prognostic marker. Moreover, HNSCC cells with p-EMT phenotype can be a useful model for investigating a nature of p-EMT.
Naito Kurio, Kumiko Kamada, Takumi Kitagawa, Yasusei Kudo, Naozumi Ishimaru and Youji Miyamoto : A case of microcystic adnexal carcinoma arising in the upper gingiva, Japanese Journal of Oral & Maxillofacial Surgery, Vol.66, No.9, 455-459, 2020.
(Summary)
<p>Microcystic adnexal carcinoma (MAC) is a rare malignant tumor of skin appendages. MAC grows slowly, but is locally aggressive. The metastatic potential is low, but the recurrence rates are very high owing to insufficient dissection. The most common location of MAC is the skin of the midface of middle-aged adults. There has been no report about MAC arising in the gingiva. We report here an extremely rare case of MAC of the upper gingiva in a 53-year-old woman. She presented to our hospital with a 6-year history of a gradually increasing gingival mass. Intraoral examination revealed a smooth, poorly circumscribed mass with white granules resembling Fordyce spots on her upper gingiva. There was no bone destruction or regional lymph node swelling. The histopathological diagnosis was a tumor of skin appendages. Tumor resection was performed. Postoperative pathological examination revealed that the tumor differentiated into hair follicles and the sweat-gland-like structures and deeply infiltrated into muscle, perineural spaces, and bone. Since the surgical margins were positive, additional resection was performed after preoperative mapping biopsy. Finally, the tumor was completely excised. No tumor recurrence or metastasis have been observed over 1 year.</p>
Natsumi Fujiwara, Hiromichi Yumoto, Koji Miyamoto, Katsuhiko Hirota, Hiromi Nakae, Saya Tanaka, Keiji Murakami, Yasusei Kudo, Kazumi Ozaki and Yoichiro Miyake : 2-Methacryloyloxyethyl phosphorylcholine (MPC)-polymer suppresses an increase of oral bacteria: a single-blind, crossover clinical trial, Clinical Oral Investigations, Vol.23, 739-746, 2019.
(Summary)
The biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC)-polymers, which mimic a biomembrane, reduce protein adsorption and bacterial adhesion and inhibit cell attachment. The aim of this study is to clarify whether MPC-polymer can suppress the bacterial adherence in oral cavity by a crossover design. We also investigated the number of Fusobacterium nucleatum, which is the key bacterium forming dental plaque, in clinical samples. This study was a randomized, placebo-controlled, single-blind, crossover study, with two treatment periods separated by a 2-week washout period. We conducted clinical trial with 20 healthy subjects to evaluate the effect of 5% MPC-polymer mouthwash after 5 h on oral microflora. PBS was used as a control. The bacterial number in the gargling sample before and after intervention was counted by an electronic bacterial counter and a culture method. DNA amounts of total bacteria and F. nucleatum were examined by q-PCR. The numbers of total bacteria and oral streptcocci after 5 h of 5% MPC-polymer treatment significantly decreased, compared to the control group. Moreover, the DNA amounts of total bacteria and F. nucleatum significantly decreased by 5% MPC-polymer mouthwash. We suggest that MPC-polymer coating in the oral cavity may suppress the oral bacterial adherence. MPC-polymer can be a potent compound for the control of oral microflora to prevent oral infection.
Kunihiro Otsuka, Akiko Yamada, Masako Saito, Aya Ushio, Mami Sato, Satoru Kisoda, Wenhua Shao, Takaaki Tsunematsu, Yasusei Kudo, Rieko Arakaki and Naozumi Ishimaru : Ascl2-Regulated Follicular Helper T Cells Promote Autoimmunity in a Murine Model for Sjögren's Syndrome., The American Journal of Pathology, Vol.189, No.12, 2414-2427, 2019.
(Summary)
mice that received neonatal thymectomy treatment demonstrated that Ascl2 contributes to the Tfh cell differentiation associated with autoimmunity during the early stages independent of Bcl6. In conclusion, our results indicate that abnormal Tfh cell differentiation via Ascl2 regulation might contribute to the pathogenesis of autoimmunity.
Tian Liu, Jing Liu, Qiuyue Chen, Shengjian Jin, Sisi Mi, Wenhua Shao, Yasusei Kudo, Sien Zeng and Guangying Qi : Expression of USP22 and the chromosomal passenger complex is an indicator of malignant progression in oral squamous cell carcinoma., Oncology Letters, Vol.17, No.2, 2040-2046, 2018.
(Summary)
Oral cancer is a common cancer of the head and neck. Oral squamous cell carcinoma (OSCC) represents almost 90% of the total cases of head and neck cancer. Ubiquitin-specific protease 22 (USP22) is a deubiquitinating hydrolase, and it is highly expressed in various types of cancer, which also typically have a poor prognosis. Aurora-B and Survivin, which belong to the chromosomal passenger complex, are also highly expressed in a number of types of cancer. In the present study, USP22 expression and its associations with Aurora-B and Survivin, and the clinicopathological features in OSCC were explored. USP22 is highly expressed in OSCC. Overexpression of USP22 is associated with lymph node metastasis and histological grade (P<0.01). Additionally, the expression of USP22 was positively associated with Aurora-B (P<0.01), Survivin (P<0.01), and Ki-67 (P<0.01). Furthermore, USP22 small interfering RNA inhibited cell growth and reduced the expression levels of Aurora-B, Survivin and Cyclin B, together with the upregulation of cyclin-dependent kinase inhibitor 1A (p21). These data suggest that USP22, Aurora-B and Survivin promote the OSCC development and may represent novel targets for OSCC diagnosis and treatment in the future.
Aya Ushio, Rieko Arakaki, Kunihiro Ohtsuka, Akiko Yamada, Takaaki Tsunematsu, Yasusei Kudo, Keiko Aota, Masayuki Azuma and Naozumi Ishimaru : CCL22-Producing Resident Macrophages Enhance T Cell Response in Sjögren's Syndrome., Frontiers in Immunology, Vol.9, 2594, 2018.
(Summary)
Macrophages (MΦs) are critical regulators of immune response and serve as a link between innate and acquired immunity. The precise mechanism of involvement of tissue-resident MΦs in the pathogenesis of autoimmune diseases is not clear. Here, using a murine model for Sjögren's syndrome (SS), we investigated the role of tissue-resident MΦs in the onset and development of autoimmunity. Two unique populations of CD11b and CD11b resident MΦs were observed in the target tissue of the SS model. Comprehensive gene expression analysis of chemokines revealed effective production of CCL22 by the CD11b MΦs. CCL22 upregulated the migratory activity of CD4 T cells by increasing CCR4, a receptor of CCL22, on T cells in the SS model. In addition, CCL22 enhanced IFN-γ production of T cells of the SS model, thereby suggesting that CCL22 may impair the local immune tolerance in the target organ of the SS model. Moreover, administration of anti-CCL22 antibody suppressed autoimmune lesions in the SS model. Finally, histopathological analysis revealed numerous CCL22-producing MΦs in the minor salivary gland tissue specimens of the SS patients. CCL22-producing tissue-resident MΦs may control autoimmune lesions by enhancing T cell response in the SS model. These results suggest that specific chemokines and their receptors may serve as novel therapeutic or diagnostic targets for SS.
Kunihiro Ohtsuka, Kohichi Yamada, Yuhji Taquahashi, Rieko Arakaki, Aya Ushio, Masako Saito, Akiko Yamada, Takaaki Tsunematsu, Yasusei Kudo, Jun Kanno and Naozumi Ishimaru : Long-term polarization of alveolar macrophages to a profibrotic phenotype after inhalation exposure to multi-wall carbon nanotubes., PLoS ONE, Vol.13, No.10, e0205702., 2018.
(Summary)
Nanomaterials are widely used in various fields. Although the toxicity of carbon nanotubes (CNTs) in pulmonary tissues has been demonstrated, the toxicological effect of CNTs on the immune system in the lung remains unclear. In this study, exposure to Taquann-treated multi-walled CNTs (T-CNTs) was performed using aerosols generated in an inhalation chamber. At 12 months after T-CNT exposure, alveolar inflammation with macrophage accumulation and hypertrophy of the alveolar walls were observed. In addition, fibrotic lesions were enhanced by T-CNT exposure. The macrophages in the bronchoalveolar lavage fluid of T-CNT-exposed mice were not largely shifted to any particular population, and were a mixed phenotype with M1 and M2 polarization. Moreover, the alveolar macrophages of T-CNT-exposed mice produced matrix metalloprotinase-12. These results suggest that T-CNT exposure promoted chronic inflammation and fibrotic lesion formation in profibrotic macrophages for prolonged periods.
Mie Kurosawa, Rieko Arakaki, Akiko Yamada, Takaaki Tsunematsu, Yasusei Kudo, J Sprent and Naozumi Ishimaru : NF κB2 Controls the Migratory Activity of Memory T Cells by Regulating Expression of CXCR4 in a Mouse Model of Sjögren's Syndrome, Arthritis & Rheumatology, Vol.69, No.11, 2193-2202, 2017.
(Summary)
Dysregulated chemokine signaling contributes to autoimmune diseases by facilitating aberrant T cell infiltration into target tissues, but the specific chemokines, receptors, and T cell populations remain largely unidentified. The aim of this study was to examine the role of the potent chemokine CXCL12 and its receptor CXCR4 in the T cell autoimmune response, using alymphoplasia (aly)/aly mice, a model of Sjögren's syndrome (SS). T cell phenotypes in the salivary gland of aly/aly mice were evaluated using immunologic analysis. An in vitro migration assay was used to assess T cell migratory activity toward several chemokines. Gene expression of chemokine receptors and transforming growth factor β receptors (TGFβRs) was measured by quantitative reverse transcription-polymerase chain reaction. The CXCR4 antagonist AMD3100 was administered to the aly/aly mice in order to evaluate its suppressive effect on autoimmune lesions. Effector memory T (TEM) cells derived from aly/aly mice demonstrated higher in vitro migratory activity toward CXCL12 than did TEM cells from aly/+ mice. CXCL12 expression was specifically up-regulated in the SS target cells of aly/aly mice. TEM cells from RelB mice, but not Nfkb1 mice, also showed high migratory activity toward CXCL12, implicating a role of the nonclassical RelB/NF-κB2 pathway in the regulation of TEM cell migration. TEM cells from aly/aly mice also overexpressed TGFβR type I (TGFβRI) and TGFβRII. The CXCR4 antagonist AMD3100 suppressed autoimmune lesions in aly/aly mice by reducing TEM cell infiltration. Our results suggest that the RelB/NF-κB2 pathway regulates T cell migration to autoimmune targets through TGFβ/TGFβR-dependent regulation of CXCL12/CXCR4 signaling. This suggests that these signaling pathways are potential therapeutic targets for the treatment of autoimmune diseases.
Hidesuke Tada, Natsumi Fujiwara, Takaaki Tsunematsu, Yoshiko Tada, Rieko Arakaki, Naofumi Tamaki, Naozumi Ishimaru and Yasusei Kudo : Preventive effects of mouthguard use while sleeping on recurrent aphthous stomatitis: Preliminary interventional study., Clinical and Experimental Dental Research, Vol.3, No.5, 198-203, 2017.
(Summary)
Recurrent aphthous stomatitis (RAS) is the most common inflammatory ulceration in the oral mucosa of otherwise healthy individuals and is often accompanied by severe pain. However, the etiology of RAS is not completely understood, and currently, no therapy can completely prevent RAS recurrence. In our clinical experience, we noticed that patients using a night guard, which is often used for bruxism treatment, did not develop RAS. Therefore, the aim of this study was to determine whether mouthguard use can suppress RAS development. The cohort of this interventional, prospective, single-center, and self-controlled study included 20 subjects who developed RAS at least once a month. The oral health of all the subjects was recorded for 60 days before and after intervention with a mouthguard. The average number of RAS incidences decreased from 5.5 to 1.0, the average days until healing decreased from 7.3 to 5.6, and the period with RAS decreased from 31.5 to 5.0 with mouthguard use. Mouthguard use may be beneficial for preventing RAS development.
KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC.
Aya Ushio, Rieko Arakaki, Hiroshi Eguchi, Fumika Hotta, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : Pathological Analysis of Ocular Lesions in a Murine Model of Sjögren's Syndrome., International Journal of Molecular Sciences, Vol.18, No.6, 2017.
(Summary)
Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by severe inflammation of exocrine glands such as the salivary and lacrimal glands. When it affects the lacrimal glands, many patients experience keratoconjunctivitis due to severely dry eyes. This study investigated the pathological and immunological characteristics of ocular lesions in a mouse model of SS. Corneal epithelial injury and hyperplasia were confirmed pathologically. The number of conjunctival mucin-producing goblet cells was significantly decreased in the SS model mice compared with control mice. Expression levels of transforming growth factor (TGF)-, interleukin (IL)-6, tumor necrosis factor (TNF)-, and C-X-C motif chemokine (CXCL) 12 were significantly higher in the corneal epithelium of the SS model mice than in control mice. Inflammatory lesions were observed in the Harderian, intraorbital, and extraorbital lacrimal glands in the SS model mice, suggesting that the ocular glands were targeted by an autoimmune response. The lacrimal glands of the SS model mice were infiltrated by cluster of differentiation (CD)4+ T cells. Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed significantly increased mRNA expression of TNF-, TGF-, CXCL9, and lysozyme in the extraorbital lacrimal glands of the SS model mice compared with control mice. These results add to the understanding of the complex pathogenesis of SS and may facilitate development of new therapeutic strategies.
Yosuke Shikama, Yasusei Kudo, Naozumi Ishimaru and Makoto Funaki : Potential Role of Free Fatty Acids in the Pathogenesis of Periodontitis and Primary Sjögren's Syndrome., International Journal of Molecular Sciences, Vol.18, No.4, 2017.
(Summary)
Clinical studies have shown that metabolic disorders such as type 2 diabetes and dyslipidemia are associated with increased risk of oral-related diseases, such as periodontitis and Sjögren's syndrome. Although changes in the immune system are critical in both of these metabolic disorders and oral-related diseases, the mechanism underlying the interaction between these diseases remains largely unknown. Obesity and type 2 diabetes are known to be associated with higher concentrations of free fatty acids in blood. Among free fatty acids, saturated fatty acids such as palmitic acid have been demonstrated to induce inflammatory responses mainly via the innate immune systems, and to be involved in the pathogenesis of type 2 diabetes in tissues such as adipose tissue, liver, pancreas, and skeletal muscle. Here, we highlight recent advances in evidence for the potential involvement of palmitic acid in the pathogenesis of periodontitis and Sjögren's syndrome, and discuss the possibility that improvement of the lipid profile could be a new strategy for the treatment of these diseases.
Satoko Kujiraoka, Takaaki Tsunematsu, Yukiko Sato, Maki Yoshida, Ayataka Ishikawa, Rei Tohyama, Michio Tanaka, Yutaka Kobayashi, Tomoyuki Kondo, Aya Ushio, Kunihiro Otsuka, Mie Kurosawa, Masako Saito, Akiko Yamada, Rieko Arakaki, Hirokazu Nagai, Hiromasa Nikai, Kengo Takeuchi, Toshitaka Nagao, Youji Miyamoto, Naozumi Ishimaru and Yasusei Kudo : Establishment and characterization of a clear cell odontogenic carcinoma cell line with EWSR1-ATF1 fusion gene., Oral Oncology, Vol.69, 46-55, 2017.
(Summary)
To the best of our knowledge, this is the first report on the establishment of a CCOC cell line. CCOC-T cells serve as a useful in vitro model for understanding the pathogenesis and nature of MOT.
Akiko Yamada, Rieko Arakaki, Masako Saito, Yasusei Kudo and Naozumi Ishimaru : Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance., Frontiers in Immunology, Vol.8, No.403, 2017.
(Summary)
Fas-mediated apoptosis contributes to physiological and pathological cellular processes, such as differentiation and survival. In particular, the roles of Fas in immune cells are complex and critical for the maintenance of immune tolerance. The precise pathways and unique functions associated with Fas/FasL-mediated signaling in the immune system are known. The dual character of Fas/FasL-mediated immune regulation that induces beneficial or harmful effects is associated with the onset or development of immune disorders. Studies on mutations in genes encoding Fas and FasL gene of humans and mice contributed to our understanding of the pathogenesis of autoimmune diseases. Here, we review the opposing functions of Fas/FasL-mediated signaling, bilateral effects of Fas/FasL on in immune cells, and complex pathogenesis of autoimmunity mediated by Fas/FasL.
Valerio Donato, Massimo Bonora, Daniele Simoneschi, Davide Sartini, Yasusei Kudo, Anita Saraf, Laurence Florens, P Michael Washburn, Matthias Stadtfeld, Paolo Pinton and Michele Pagano : The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells., Nature Cell Biology, Vol.19, No.4, 341-351, 2017.
(Summary)
Self-renewing naive mouse embryonic stem cells (mESCs) contain few mitochondria, which increase in number and volume at the onset of differentiation. KBP (encoded by Kif1bp) is an interactor of the mitochondrial-associated kinesin Kif1B. We found that TDH, responsible for mitochondrial production of acetyl-CoA in mESCs, and the acetyltransferase GCN5L1 cooperate to acetylate Lys501 in KBP, allowing its recognition by and degradation via Fbxo15, an F-box protein transcriptionally controlled by the pluripotency core factors and repressed following differentiation. Defects in KBP degradation in mESCs result in an unscheduled increase in mitochondrial biogenesis, enhanced respiration and ROS production, and inhibition of cell proliferation. Silencing of Kif1B reverts the aberrant increase in mitochondria induced by KBP stabilization. Notably, following differentiation, Kif1bp(-/-) mESCs display impaired expansion of the mitochondrial mass and form smaller embryoid bodies. Thus, KBP proteolysis limits the accumulation of mitochondria in mESCs to preserve their optimal fitness, whereas KBP accumulation promotes mitochondrial biogenesis in differentiating cells.
Toshinori Ando, Yasusei Kudo, Shinji Iizuka, Takaaki Tsunematsu, Hanako Umehara, Madhu Shrestha, Toshihiro Matsuo, Tadahiko Kubo, Shouji Shimose, Koji Arihiro, Ikuko Ogawa, Mitsuo Ochi and Takashi Takata : Ameloblastin induces tumor suppressive phenotype and enhances chemosensitivity to doxorubicin via Src-Stat3 inactivation in osteosarcoma., Scientific Reports, Vol.7, 40187, 2017.
(Summary)
Ameloblastin (AMBN), the most abundant non-amelogenin enamel matrix protein, plays a role in ameloblast differentiation. Previously, we found that AMBN promoted osteogenic differentiation via the interaction between CD63 and integrin 1, leading to the inactivation of Src; however, how AMBN affects the malignant behavior of osteosarcoma is still unclear. Osteosarcoma affects the bone and is associated with poor prognosis because of the high rate of pulmonary metastases and drug resistance. Here we demonstrated that stable overexpression of AMBN induced apoptosis and suppressed colony formation and cell migration via the inactivation of Src-Stat3 pathway in human osteosarcoma cells. Moreover, AMBN induced chemosensitivity to doxorubicin. Thus, AMBN induced a tumor suppressive phenotype and chemosensitivity to doxorubicin via the AMBN-Src-Stat3 axis in osteosarcoma. Indeed, immunohistochemical expression of AMBN was significantly correlated with better outcome of osteosarcoma patients. Our findings suggest that AMBN can be a new prognostic marker and therapeutic target for osteosarcoma combined with conventional doxorubicin treatment.
Takashi Izawa, Rieko Arakaki, Hiroki Mori, Takaaki Tsunematsu, Yasusei Kudo, Eiji Tanaka and Naozumi Ishimaru : The nuclear receptor AhR controls bone homeostasis by regulating osteoclast differentiation via the RANK/c-Fos signaling axis., The Journal of Immunology, Vol.197, No.12, 4639-4650, 2016.
(Summary)
The aryl hydrocarbon receptor (AhR) pathway plays a key role in receptor activator of NF-κB ligand (RANKL)-mediated osteoclastogenesis. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow-derived osteoclasts was upregulated by RANKL at an earlier stage than was the expression of signature osteoclast genes such as those encoding cathepsin K and NFAT, cytoplasmic, calcineurin-dependent 1. In response to RANKL, bone marrow macrophages isolated from AhR(-/-) mice exhibited impaired phosphorylation of Akt and MAPK as well as NF-κB, whereas their response to M-CSF remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in an RANKL/c-Fos-dependent manner. Furthermore, ligand activation of AhR by the smoke toxin benzo[a]pyrene accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR(-/-) mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest that the RANKL/AhR/c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone.
Takaaki Tsunematsu, Natsumi Fujiwara, Maki Yoshida, Yukihiro Takayama, Satoko Kujiraoka, Guangying Qi, Masae Kitagawa, Tomoyuki Kondo, Akiko Yamada, Rieko Arakaki, Mutsumi Miyauchi, Ikuko Ogawa, Yoshihiro Abiko, Hiroki Nikawa, Shinya Murakami, Takashi Takata, Naozumi Ishimaru and Yasusei Kudo : Human odontogenic epithelial cells derived from epithelial rests of Malassez possess stem cell properties., Laboratory Investigation; a Journal of Technical Methods and Pathology, 2016.
(Summary)
Epithelial cell rests of Malassez (ERM) are quiescent epithelial remnants of the Hertwig's epithelial root sheath (HERS) that are involved in the formation of tooth roots. ERM cells are unique epithelial cells that remain in periodontal tissues throughout adult life. They have a functional role in the repair/regeneration of cement or enamel. Here, we isolated odontogenic epithelial cells from ERM in the periodontal ligament, and the cells were spontaneously immortalized. Immortalized odontogenic epithelial (iOdE) cells had the ability to form spheroids and expressed stem cell-related genes. Interestingly, iOdE cells underwent osteogenic differentiation, as demonstrated by the mineralization activity in vitro in mineralization-inducing media and formation of calcification foci in iOdE cells transplanted into immunocompromised mice. These findings suggest that a cell population with features similar to stem cells exists in ERM and that this cell population has a differentiation capacity for producing calcifications in a particular microenvironment. In summary, iOdE cells will provide a convenient cell source for tissue engineering and experimental models to investigate tooth growth, differentiation, and tumorigenesis.Laboratory Investigation advance online publication, 1 August 2016; doi:10.1038/labinvest.2016.85.
Chieko Sugawara, Akira Takahashi, Fumiaki Kawano, Yasusei Kudo, Naozumi Ishimaru and Youji Miyamoto : Intraoral Ultrasonography of Tongue Mass Lesions, Dento Maxillo Facial Radiology, Vol.45, No.5, 20150362, 2016.
(Summary)
To demonstrate the usefulness of intraoral ultrasonography (IOUS) for tongue mass lesions, we analyzed surgery cases excluding squamous-cell carcinoma and leukoplakia and compared IOUS and pathological findings. We used the hospital information system and Radiology Information System to evaluate the IOUS and pathological findings of patients who underwent surgeries for tongue masses in the past 11 years. Surgeries for the tongues were performed in 268 cases. Imaging examinations were carried out in 52 (19.4%) cases including 42 (15.7%) cases by IOUS. The pathological results of the surgeries were as follows: 36 cases were inflammatory lesions, 74 cases were tumours, 131 cases were hyperplasia, 8 cases were cystic lesions and 19 cases were other miscellaneous lesions. On the other hand, the number of patients who received IOUS in the same period was 87, and 42 of them had surgeries. In 32 out of the 42 (76.2%) cases, pre-operative IOUS features matched with pathological results. Most of the haemangiomas and lipomas could be diagnosed by IOUS alone. IOUS of the tongue revealed the nature of the lesions including the border, size, location, depth, the presence or absence of a capsule and the internal structure including vascularity of the mass. The ultrasonographic findings well reflected the histological findings. IOUS is a simple and useful technique that provides additional information beyond inspection, clarifying the internal structure, blood flow and relationships with the adjacent tissues. In this article, we indicated 11 representative cases (fibrous polyp, haemangioma, pyogenic granuloma, lipoma, liposarcoma, chondroma, lymphangioma, schwannoma, neurofibroma, pleomorphic adenoma and amyloidosis) to show the usefulness of IOUS.
Junichi Hamada, Katsutoshi Shoda, Kiyoshi Masuda, Yuji Fujita, Takuya Naruto, Tomohiro Kohmoto, Yuko Miyakami, Miki Watanabe, Yasusei Kudo, Hitoshi Fujiwara, Daisuke Ichikawa, Eigo Otsuji and Issei Imoto : Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma., Oncotarget, Vol.7, No.13, 17111-17128, 2016.
(Summary)
T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein involved in many regulatory aspects of mRNA metabolism. Here, we report previously unknown tumor-promoting activity of TIA1, which seems to be associated with its isoform-specific molecular distribution and regulation of a set of cancer-related transcripts, in esophageal squamous cell carcinoma (ESCC). Immunohistochemical overexpression of TIA1 ectopically localized in the cytoplasm of tumor cells was an independent prognosticator for worse overall survival in a cohort of 143 ESCC patients. Knockdown of TIA1 inhibited proliferation of ESCC cells. By exogenously introducing each of two major isoforms, TIA1a and TIA1b, only TIA1a, which was localized to both the nucleus and cytoplasm, promoted anchorage-dependent and anchorage-independent ESCC cell proliferation. Ribonucleoprotein immunoprecipitation, followed by microarray analysis or massive-parallel sequencing, identified a set of TIA1-binding mRNAs, including SKP2 and CCNA2. TIA1 increased SKP2 and CCNA2 protein levels through the suppression of mRNA decay and translational induction, respectively. Our findings uncover a novel oncogenic function of TIA1 in esophageal tumorigenesis, and implicate its use as a marker for prognostic evaluation and as a therapeutic target in ESCC.
Mariko Obayashi, Maki Yoshida, Takaaki Tsunematsu, Ikuko Ogawa, Tomonori Sasahira, Hiroki Kuniyasu, Issei Imoto, Yoshimitsu Abiko, Dan Xu, Saori Fukunaga, Hidetoshi Tahara, Yasusei Kudo, Toshitaka Nagao and Takashi Takata : microRNA-203 suppresses invasion and epithelial-mesenchymal transition induction via targeting NUAK1 in head and neck cancer., Oncotarget, Vol.7, No.7, 8223-8239, 2016.
(Summary)
Head and neck squamous cell carcinoma (HNSCC) has a high capacity for invasion. To identify microRNAs (miRNAs) that regulate HNSCC invasion, we compared miRNA expression profiles between a parent HNSCC cell line and a highly invasive clone. The miR-200 family and miR-203 were downregulated in the clone. Here we focused on the role of miR-203 in invasion and epithelial-mesenchymal transition (EMT) induction in HNSCC. miR-203 was downregulated during EMT induction. Moreover, ectopic overexpression of miR-203 suppressed the invasion and induced mesenchymal-epithelial transition (MET) in HNSCC cells. Interestingly, we identified NUAK family SNF1-like kinase 1 (NUAK1) as a novel target gene of miR-203 by cyclopedic analysis using anti-Ago2 antibody. Increased expression of NUAK1 was observed during EMT induction, and ectopic expression of miR-203 delayed EMT induction by suppressing NUAK1 expression. Moreover, NUAK1 overexpression promoted the invasion of HNSCC cells. Importantly, NUAK1 expression was well correlated with poor differentiation, invasiveness, and lymph node metastasis in HNSCC cases. Overall, miR-203 has a tumor-suppressing role in invasion and EMT induction by targeting NUAK1 in HNSCC, suggesting miR-203 as a potential new diagnostic and therapeutic target for the treatment of HNSCC.
Akiko Yamada, Aya Ushio, Rieko Arakaki, Takaaki Tsunematsu, Yasusei Kudo, Yoshio Hayashi and Naozumi Ishimaru : Impaired expansion of regulatory T cells in a neonatal thymectomy-induced autoimmune mouse model., The American Journal of Pathology, Vol.185, No.11, 2886-2897, 2015.
(Summary)
Neonatal thymectomy in certain mouse strains is known to induce organ-specific autoimmunity due to impaired functions of T cells, including Foxp3(+) regulatory T (Treg) cells in the thymus. The precise mechanism underlying the induction of autoimmunity by neonatal thymectomy remains unclear. One possibility is that depletion of Treg cells breaks down peripheral tolerance. We examined the functions of Treg cells by using a murine Sjögren syndrome model of NFS/sld mice that underwent neonatal thymectomy. The ratio of Treg cells to effector memory phenotype T cells in thymectomy mice was significantly lower than that of nonthymectomy mice. In addition, in vitro induction of peripherally induced Treg cells by transforming growth factor-β (TGF-β) using naive T cells from Sjögren syndrome model mice was severely impaired. The mRNA expression of TGF-β receptor I and II and Smad3 and -4 in the TGF-β-induced signal transduction pathway of Treg cells in this Sjögren syndrome model were lower than those of control mice. In addition, Treg cells in this Sjögren syndrome model exhibited an interferon-γ-producing Th1-like phenotype that resembled effector T cells. In conclusion, these results suggest that abnormal expansion and differentiation of Treg cells and inflammatory cytokines produced by Treg cells contribute to the development of autoimmunity.
Takaaki Tsunematsu, Rieko Arakaki, Akiko Yamada, Naozumi Ishimaru and Yasusei Kudo : The non-canonical role of Aurora-A in DNA replication., Frontiers in Oncology, Vol.96, No.4, 468-480, 2015.
(Summary)
Aurora-A is a well-known mitotic kinase that regulates mitotic entry, spindle formation, and chromosome maturation as a canonical role. During mitosis, Aurora-A protein is stabilized by its phosphorylation at Ser51 via blocking anaphase-promoting complex/cyclosome-mediated proteolysis. Importantly, overexpression and/or hyperactivation of Aurora-A is involved in tumorigenesis via aneuploidy and genomic instability. Recently, the novel function of Aurora-A for DNA replication has been revealed. In mammalian cells, DNA replication is strictly regulated for preventing over-replication. Pre-replication complex (pre-RC) formation is required for DNA replication as an initiation step occurring at the origin of replication. The timing of pre-RC formation depends on the protein level of geminin, which is controlled by the ubiquitin-proteasome pathway. Aurora-A phosphorylates geminin to prevent its ubiquitin-mediated proteolysis at the mitotic phase to ensure proper pre-RC formation and ensuing DNA replication. In this review, we introduce the novel non-canonical role of Aurora-A in DNA replication.
Yosuke Shikama, Yasusei Kudo, Naozumi Ishimaru and Makoto Funaki : Possible involvement of palmitate in pathogensis of periodontitis., Journal of Cellular Physiology, Vol.230, No.12, 2981-2989, 2015.
Akihiko Iwasa, Rieko Arakaki, Naoko Honma, Aya Ushio, Akiko Yamada, Tomoyuki Kondo, Emi Kurosawa, Satoko Kujiraoka, Takaaki Tsunematsu, Yasusei Kudo, Eiji Tanaka, Noriko Yoshimura, Nobuhiro Harada, Yoshio Hayashi and Naozumi Ishimaru : Aromatase controls Sjögren syndrome-like lesions through monocyte chemotactic protein-1 in target organ and adipose tissue-associated macrophages., The American Journal of Pathology, Vol.185, No.1, 151-161, 2015.
(Summary)
Several autoimmune diseases are known to develop in postmenopausal women. However, the mechanism by which estrogen deficiency influences autoimmunity is unknown. Aromatase is an enzyme that converts androgens to estrogens. Herein, we used female aromatase gene knockout (ArKO) mice as a model of estrogen deficiency to investigate the molecular mechanism that underlies the onset and development of autoimmunity. Histological analyses showed that inflammatory lesions in the lacrimal and salivary glands of ArKO mice increased with age. Adoptive transfer of spleen cells or bone marrow cells from ArKO mice into recombination activating gene 2 knockout mice failed to induce the autoimmune lesions. Expression of mRNA encoding proinflammatory cytokines and monocyte chemotactic protein-1 increased in white adipose tissue of ArKO mice and was significantly higher than that in wild-type mice. Moreover, an increased number of inflammatory M1 macrophages was observed in white adipose tissue of ArKO mice. A significantly increased monocyte chemotactic protein-1 mRNA expression of the salivary gland tissue in ArKO was found together with adiposity. Furthermore, the autoimmune lesions in a murine model of Sjögren syndrome were exacerbated by administration of an aromatase inhibitor. These results suggest that aromatase may play a key role in the pathogenesis of Sjögren syndrome-like lesions by controlling the target organ and adipose tissue-associated macrophage.
Rieko Arakaki, Hiroshi Eguchi, Akiko Yamada, Yasusei Kudo, Akihiko Iwasa, Enkhmaa Tserennadmid, Hotta Fumika, Mitamura-Aizawa Sayaka, Yoshio Hayashi and Naozumi Ishimaru : Anti-Inflammatory Effects of Rebamipide Eyedrop Administration on Ocular Lesions in a Murine Model of Primary Sjögren's Syndrome., PLoS ONE, Vol.9, No.5, e98390, 2014.
(Summary)
Topical therapy is effective for dry eye, and its prolonged effects should help in maintaining the quality of life of patients with dry eye. We previously reported that the oral administration of rebamipide (Reb), a mucosal protective agent, had a potent therapeutic effect on autoimmune lesions in a murine model of Sjögren's syndrome (SS). However, the effects of topical treatment with Reb eyedrops on the ocular lesions in the murine model of SS are unknown. Reb eyedrops were administered to the murine model of SS aged 4-8 weeks four times daily. Inflammatory lesions of the extraorbital and intraorbital lacrimal glands and Harderian gland tissues were histologically evaluated. The direct effects of Reb on the lacrimal glands were analyzed using cultured lacrimal gland cells. Tear secretions of Reb-treated mice were significantly increased compared with those of untreated mice. In addition to the therapeutic effect of Reb treatment on keratoconjunctivitis, severe inflammatory lesions of intraorbital lacrimal gland tissues in this model of SS were resolved. The mRNA expression levels of IL-10 and mucin 5Ac in conjunctival tissues from Reb-treated mice was significantly increased compared with those of control mice. Moreover, lactoferrin production from lacrimal gland cells was restored by Reb treatment. Topical Reb administration had an anti-inflammatory effect on the ocular autoimmune lesions in the murine model of SS and a protective effect on the ocular surfaces.
Ashrin Nur Meinar, Rieko Arakaki, Akiko Yamada, Tomoyuki Kondo, Mie Kurosawa, Yasusei Kudo, Megumi Watanabe, Tetsuo Ichikawa, Yoshio Hayashi and Naozumi Ishimaru : A critical role for thymic stromal lymphopoietin in nickel-induced allergy in mice., The Journal of Immunology, Vol.192, No.9, 4025-4031, 2014.
(Summary)
Ni is the most frequent cause of contact allergy induced by metals. However, the underlying mechanism of this induction is unknown. Our previous research demonstrates that activation of dendritic cells (DCs) through p38MAPK/MKK6 is required for Ni-induced allergy in mice. In the current study, we investigated the cellular and molecular mechanisms underlying Ni-induced allergy using a mouse model that involves injecting Ni into the ear, with or without Freund's incomplete or complete adjuvants. Nickel had greater potential to cause allergic reactions compared with palladium and gold. Among the proteins expressed at higher levels in mice with Ni-induced allergy, we focused on thymic stromal lymphopoietin (TSLP), which is produced in abundance by keratinocytes. We detected increased expression of the TSLP receptor (TSLPR) in DCs from cervical lymph nodes of mice with Ni-induced allergy, suggesting that DCs in ear tissues were activated through TSLPR signaling induced by keratinocyte-derived TSLP. Furthermore, delayed-type hypersensitivity reactions in mice with Ni-induced allergy were decreased significantly by injection of a Tslp-short interfering RNA along with atelocollagen in the ear skin. These results suggest that Ni allergy may be triggered by a TSLP/TSLPR-mediated interaction between epithelial and immune cells.
J Simon Conway, Kenji Izuhara, Yasusei Kudo, Judith Litvin, Roger Markwald, Gaoliang Ouyang, R Joseph Arron, J Cecile T Holweg and Akira Kudo : The role of periostin in tissue remodeling across health and disease., Cellular and Molecular Life Sciences, Vol.71, No.7, 1279-1288, 2013.
(Summary)
Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial-mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury.
Natsumi Shimizu, Izumi Nakako Nakajima, Takaaki Tsunematsu, Ikuko Ogawa, Hidehiko Kawai, Ryoichi Hirayama, Akira Fujimori, Akiko Yamada, Ryuichi Okayasu, Naozumi Ishimaru, Takashi Takata and Yasusei Kudo : Selective enhancing effect of early mitotic inhibitor 1 depletion on the sensitivity of doxorubicin or X-ray treatment in human cancer cells., The Journal of Biological Chemistry, 2013.
(Summary)
Chemotherapy and radiation in addition to surgery has proven useful in a number of different cancer types, but the effectiveness in normal tissue cannot be avoided in these therapies. To improve the effectiveness of these therapies selectively in cancer tissue is important for avoiding side-effects. Early mitotic inhibitor 1 (Emi1) is known to have the function to inhibit anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex, which ubiquitylates the cell cycle related proteins. It recently has been shown that Emi1 knockdown prevents transition from S to G2 phase by downregulating geminin via APC/C activation. At present anticancer drugs for targeting DNA synthesis to interfere with rapidly dividing cells commonly are used. As Emi1 depletion interferes with completion of DNA synthesis in cancer cells, we thought that Emi1 knockdown might enhance the sensitivity for anticancer agents. Here we confirmed that Emi1 siRNA induced polyploidy for preventing transition from S to G2 phase in several cancer cell lines. Then, we treated Emi1 depleted cells with doxorubicin. Interestingly, increased apoptotic cells were observed after doxorubicin treatment in Emi1 siRNA treated cancer cells. In addition, Emi1 depletion enhanced the sensitivity of X-rays irradiation in cancer cells. Importantly, synergistic effect of Emi1 knockdown in these combination therapies was not observed in normal cells. These results suggest that Emi1 siRNA can be a useful tool for enhancing of sensitivity of cancer cells to anticancer reagents and radiation.
Yosuke Shikama, Naozumi Ishimaru, Yasusei Kudo, Yukiko Bandou, N Aki, Yoshio Hayashi and Makoto Funaki : Effects of Free Fatty Acids on Human Salivary Gland Epithelial Cells., Journal of Dental Research, Vol.92, No.6, 540-546, 2013.
(Summary)
Obesity and type 2 diabetes (T2D) are characterized by decreased insulin sensitivity and higher concentrations of free fatty acids (FFAs) in plasma. Among FFAs, saturated fatty acids (SFAs), such as palmitate, have been proposed to promote inflammatory responses. Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammatory mononuclear cell infiltration and destruction of epithelial cells in the salivary and lacrimal glands. IL-6 production and -fodrin degradation are increased in salivary gland epithelial cells of patients with primary SS. Although previous studies have shown a link between SS and either dyslipidemia or T2D, little is known about the clinical significance of FFAs in primary SS. Here we report that SFAs, but not unsaturated fatty acids, induced IL-6 production via NF-B and p38 MAPK activation in human salivary gland epithelial cells. Moreover, palmitate induced apoptosis and -fodrin degradation by caspase-3 activation. Unlike salivary gland epithelial cells, induction of IL-6 production and the degradation of -fodrin in response to palmitate were undetectable in squamous carcinoma cells and keratinocytes. Taken together, SFAs induced IL-6 production and -fodrin degradation in salivary gland epithelial cells, implicating a potential link between the pathogenesis of primary SS and SFAs level in plasma.
Hiroko Hatano, Ikuko Ogawa, Hideo Shigeishi, Yasusei Kudo, Kouji Ohta, Koichiro Higashikawa, Masaaki Takechi, Takashi Takata and Nobuyuki Kamata : Expression of receptor for hyaluronan-mediated motility (RHAMM) in ossifying fibromas., Histology and Histopathology, Vol.28, No.4, 473-480, 2013.
(Summary)
Fibro-osseous lesions of the jaw are poorly understood because of a significant overlap of clinical, radiological and histological features among the various types, though they present distinct patterns of disease progression. An ossifying fibroma is associated with significant cosmetic and functional disturbances, as it shows expansive proliferation. Thus, it is important to establish a specific marker, as well as clearly elucidate its etiology for diagnosis and proper treatment. We previously established immortalized cell lines from human ossifying fibromas of the jaw and found that they highly expressed the receptor for hyaluronan (HA)-mediated motility (RHAMM). In this study, we examined the expression of RHAMM mRNA in 65 fibro-osseous lesions, including ossifying fibroma, fibrous dysplasia and osseous dysplasia, as well as 5 normal jaws, using real-time RT-PCR and immunohistochemistry assays. RHAMM mRNA and protein expression were significantly elevated in the ossifying fibroma specimens. These results suggest that detection of upregulated RHAMM expression in an ossifying fibroma assists with differential diagnosis and has a key role in elucidation of its pathophysiology.
Ritsuko 徳永 律子 Oura, Rieko Arakaki, Akiko Yamada, Yasusei Kudo, Eiji Tanaka, Yoshio Hayashi and Naozumi Ishimaru : Induction of Rapid T Cell Death and Phagocytic Activity by Fas-Deficient lpr Macrophages., The Journal of Immunology, 2013.
(Summary)
Peripheral T cells are maintained by the apoptosis of activated T cells through the Fas-Fas ligand system. Although it is well known that normal T cells fail to survive in the Fas-deficient immune condition, the molecular mechanism for the phenomenon has yet to be elucidated. In this study, we demonstrate that rapid cell death and clearance of normal T cells were induced by Fas-deficient lpr macrophages. Transfer of normal T cells into lpr mice revealed that Fas expression on donor T cells was promptly enhanced through the IFN-/IFN-R. In addition, Fas ligand expression and phagocytic activity of lpr macrophages were promoted through increased NF-B activation. Controlling Fas expression on macrophages plays an essential role in maintaining T cell homeostasis in the peripheral immune system. Our data suggest a critical implication to the therapeutic strategies such as transplantation and immunotherapy for immune disorder or autoimmunity related to abnormal Fas expression.
Takaaki Tsunematsu, Yoshihiro Takihara, Naozumi Ishimaru, Michele Pagano, Takashi Takata and Yasusei Kudo : Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis., Nature Communications, Vol.4, 2013.
(Summary)
Geminin, an essential factor for DNA replication, directly binds to the licensing factor Cdt1 and inhibits pre-replicative complex formation to prevent re-replication. In G1, geminin levels are controlled by the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex, which targets geminin for proteasomal degradation to allow pre-replicative complex formation. Conversely, from S to G2, geminin is stabilized due to APC/C ubiquitin ligase complex inhibition, ensuring the inhibition of pre-replicative complex formation. However, mitotic regulation of geminin has hitherto not been described. Here we show that Aurora-A phosphorylates geminin on Thr25 during M phase, and this event induces geminin stabilization by preventing its APC/C ubiquitin ligase complex-mediated degradation during mitosis. In turn, stabilized geminin inhibits SCF(Skp2)-mediated degradation of Cdt1 to ensure pre-replicative complex formation in the ensuing S phase. The Aurora-A-geminin-Cdt1 axis therefore represents a critical regulator of proper DNA replication.
BACKGROUND: Although autoimmunity in MRL/lpr mice occurs due to a defect in Fas-mediated cell death of T cells, the role of Fas-independent apoptosis in pathogenesis has rarely been investigated. We have recently reported that receptor activator of nuclear factor (NF)-B ligand (RANKL)-activated dendritic cells (DCs) play a key role in the pathogenesis of rheumatoid arthritis (RA) in MRL/lpr mice. We here attempted to establish a new therapeutic strategy with RANKL-activated DCs in RA by controlling apoptosis of peripheral T cells. Repeated transfer of RANKL-activated DCs into MRL/lpr mice was tested to determine whether this had a therapeutic effect on autoimmunity. METHODS AND FINDING: Cellular and molecular mechanisms of Fas-independent apoptosis of T cells induced by the DCs were investigated by in vitro and in vivo analyses. We demonstrated that repeated transfers of RANKL-activated DCs into MRL/lpr mice resulted in therapeutic effects on RA lesions and lymphoproliferation due to declines of CD4(+) T, B, and CD4(-)CD8(-) double negative (DN) T cells. We also found that the Fas-independent T-cell apoptosis was induced by a direct interaction between tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) on T cells and TRAIL on Fas-deficient DCs in MRL/lpr mice. CONCLUSION: These results strongly suggest that a novel Fas-independent apoptosis pathway in T cells maintains peripheral tolerance and thus controls autoimmunity in MRL/lpr mice.
Matrix metalloproteinases (MMPs) are extracellular zinc-dependent endopeptidases involved in the degradation and remodeling of extracellular matrix (ECM) in physiological and pathological processes. MMPs also have a role in cell proliferation, migration, differentiation, angiogenesis and apoptosis. We previously identified cancer invasion-related factors by comparing the gene expression profiles between parent and highly invasive clone of cancer cells. Matrix metalloproteinase-13 (MMP-13) was identified as a common upregulated gene by cancer invasion-related factors. Although MMP-13 slightly promoted tumor invasion, we found that MMP-13 was involved in tumor angiogenesis. Conditioned media from MMP-13-overexpressing cells promoted capillary formation of immortalized human umbilical vein endothelial cells (HUVECs). Furthermore, treatment with recombinant MMP-13 protein enhanced capillary tube formation both in vitro and in vivo. MMP-13-promoted capillary tube formation was mediated by activation of focal adhesion kinase (FAK) and ERK. Interestingly, MMP-13 promoted the secretion of VEGF-A from fibroblasts and endothelial cells. By immunohistochemical analysis, we found a possible correlation between MMP-13 expression and the number of blood vessels in human cancer cases. In summary, these findings suggest that MMP-13 may directly and indirectly promote tumor angiogenesis.
Yasusei Kudo, Shinji Iizuka, Maki Yoshida, Thao Phuong Nguyen, M Samadarani B S Siriwardena, Takaaki Tsunematsu, Mariko Ohbayashi, Toshinori Ando, Daijiro Hatakeyama, Toshiyuki Shibata, Keiichi Koizumi, Masahiro Maeda, Naozumi Ishimaru, Ikuko Ogawa and Takashi Takata : Periostin directly and indirectly promotes tumor lymphangiogenesis of head and neck cancer., PLoS ONE, Vol.7, No.8, e44488, 2012.
(Summary)
Our findings suggest that periostin itself as well as periostin-induced upregulation of VEGF-C may promote lymphangiogenesis. We suggest that periostin may be a marker for prediction of malignant behaviors in HNSCC and a potential target for future therapeutic intervention to obstruct tumoral lymphatic invasion and lymphangiogenesis in HNSCC patients.
Fabio Bucchieri, Alberto Fucarino, Marino Antonella Gammazza, Alessandro Pitruzzella, Vito Marcianò, Carlo Paderni, Viviana Caro De, Gabriella Maria Siragusa, Lorenzo Muzio Lo, T Stephen Holgate, E Donna Davies, Felicia Farina, Giovanni Zummo, Yasusei Kudo, Libero Italo Giannola and Giuseppina Campisi : Medium-term culture of normal human oral mucosa: a novel three-dimensional model to study the effectiveness of drugs administration., Current Pharmaceutical Design, Vol.18, No.34, 5421-5430, 2012.
(Summary)
Tissue-engineered oral mucosal equivalents have been developed for in vitro studies for a few years now. However, the usefulness of currently available models is still limited by many factors, mainly the lack of a physiological extracellular matrix (ECM) and the use of cell populations that do not reflect the properly differentiated cytotypes of the mucosa of the oral cavity. For this reason, we have developed a novel three-dimensional culture model reflecting the normal architecture of the human oral mucosa, with the main aim of creating a better in vitro model where to test cellular responses to drugs administration. This novel 3D cell culture model (3D outgrowth) was set up using an artificial extracellular matrix (MatrigelTM), allowing the interactions required for proper differentiation of the various citotypes which form the mucosal layer. Biopsies of human oral mucosa, in fragments of about 0.5 mm3, were placed onto 6.5mm Transwells, covered with MatrigelTM and grown in a specific culture medium. A gradual formation of an architectural structure similar to that of the in vivo oral mucosa was observed. Transmission electron and confocal microscopy were employed to characterize the newly developed model: the cell components (keratinocytes and fibroblasts) differentiated properly within the outgrowth and reconstituted, in vitro, the physiological structure of the human oral mucosa, including a stratified non-keratinized squamous layer composed of four different layers, a proper basal membrane and a lamina propria where fibroblasts produce ECM. Moreover, keratinocytes expressed CK5, CK13, CK19 and E-cadherin, whereas fibroblasts expressed collagen type I and IV, laminin and fibronectin. 3D outgrowths could be considered a valid alternative to animal models, and provide useful information for researchers interested in studying the responses of the human oral mucosa to locally delivered drugs or other exogenous treatments.
Vincenzo D'Angiolella, Valerio Donato, M Frances Forrester, Yeon-Tae Jeong, Claudia Pellacani, Yasusei Kudo, Anita Saraf, Laurence Florens, P Michael Washburn and Michele Pagano : Cyclin F-Mediated Degradation of Ribonucleotide Reductase M2 Controls Genome Integrity and DNA Repair., Cell, Vol.149, No.5, 1023-1034, 2012.
(Summary)
F-box proteins are the substrate binding subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes. Using affinity purifications and mass spectrometry, we identified RRM2 (the ribonucleotide reductase family member 2) as an interactor of the F-box protein cyclin F. Ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides (dNTPs), which are necessary for both replicative and repair DNA synthesis. We found that, during G2, following CDK-mediated phosphorylation of Thr33, RRM2 is degraded via SCF(cyclin F) to maintain balanced dNTP pools and genome stability. After DNA damage, cyclin F is downregulated in an ATR-dependent manner to allow accumulation of RRM2. Defective elimination of cyclin F delays DNA repair and sensitizes cells to DNA damage, a phenotype that is reverted by expressing a nondegradable RRM2 mutant. In summary, we have identified a biochemical pathway that controls the abundance of dNTPs and ensures efficient DNA repair in response to genotoxic stress.
Toshihiro Inubushi, Aki Kawazoe, Mutsumi Miyauchi, Yasusei Kudo, Min Ao, Atsushi Ishikado, Taketoshi Makino and Takashi Takata : Molecular mechanisms of the inhibitory effects of bovine Lactoferrin on LPS-mediated osteoclastogenesis., The Journal of Biological Chemistry, 2012.
(Summary)
Lactoferrin (LF) is an important modulator of the immune response and inflammation. It has also been implicated in the regulation of bone tissue. In our previous study, we demonstrated that bovine LF (bLF) reduces LPS-induced bone resorption through a reduction of TNF-production by osteoblasts. However, it was not known how bLF inhibits LPS-mediated TNF- and RANKL production in osteoblasts. In the present study, we show that bLF impairs LPS-mediated TNF- and RANKL (Receptor activator of nuclear factor kappa-B ligand) prodiction. bLF inhibited LPS-mediated osteoclastogenesis via osteoblasts in a co-culture system. Furthermore, bLF pretreatment inhibited LPS-induced NFB DNA binding activity, as well as IB and IKK phosphorylation. MAP kinase activation was also inhibited by bLF pretreatment. However, bLF pretreatment failed to block the degradation of IRAK1 (iterleukin-1 receptor-associated kinase 1), which is an essential event following its activation. Remarkably, we found that bLF pretreatment inhibited LPS-mediated K63-linked polyubiquitination of TNF receptor-associated factor 6 (TRAF6). We also found that endocytosed bLF bound to endogenous TRAF6. In addition, bLF inhibited IL-1 and Flagellin induced TRAF6-dependent activation of the NFB signaling pathway. Collectively, our findings demonstrate that bLF inhibits NFB and MAP kinase activation, which play critical roles in chronic inflammatory disease, by interfering with the TRAF6 polyubiquitination process. Thus, bLF could be a potent therapeutic agent for inflammatory diseases associated with bone destruction, such as periodontitis and rheumatoid arthritis.
H Hatano, Yasusei Kudo, I Ogawa, H Shimasue, H Shigeishi, K Ohta, K Higashikawa, Masaaki Takechi, Takashi Takata and Nobuyuki Kamata : Establishment of mesenchymal cell line derived from human developing odontoma., Oral Diseases, 2012.
(Summary)
Oral Diseases (2012) Objectives: An odontoma, which shows proliferating odontogenic epithelium and mesenchymal tissue, is one of the most common odontogenic tumors encountered. These are commonly found in tooth-bearing regions, although the etiology remains unknown. There are no previous reports of an established line of immortalized human odontoma cells. Methods: Using odontoma fragments obtained from a girl treated at our department, we established an immortalized human odontoma cell line and investigated cell morphology, dynamic proliferation, the presence of contamination, and karyotype. Moreover, cell characterization was examined using osteogenic and odontogenic markers. Results: We successfully established a mesenchymal odontoma cell (mOd cells). The cells were found to be fibroblastic and had a high level of telomerase activity. Cell growth was confirmed after more than 200 population doublings without significant growth retardation. mOd cells expressed mRNA for differentiation markers, including collagen type I (COLI), alkaline phosphatase, bone sialoprotein, osteopontin, osteocalcin, cementum-derived protein (CP-23), dentin sialophosphoprotein (DSPP), and distal-less homeobox 3 (DLX3), as well as bone morphogenetic proteins (BMPs). In addition, they showed a high level of calcified nodule formation activity in vitro. Conclusions: We successfully established a cell line that may be useful for investigating the mechanisms of normal odontogenesis as well as characteristics of odontoma tumors.
M Teresa Desrochers, Yulia Shamis, Addy Alt-Holland, Yasusei Kudo, Takashi Takata, Guangwen Wang, Laurie Jackson-Grusby and A Jonathan Garlick : The 3D tissue microenvironment modulates DNA methylation and E-cadherin expression in squamous cell carcinoma., Epigenetics, Vol.7, No.1, 2012.
(Summary)
The microenvironment plays a significant role in human cancer progression. However, the role of the tumor microenvironment in the epigenetic control of genes critical to cancer progression remains unclear. As transient E-cadherin expression is central to many stages of neoplasia and is sensitive to regulation by the microenvironment, we have studied if microenvironmental control of E-cadherin expression is linked to transient epigenetic regulation of its promoter, contributing to the unstable and reversible expression of E-cadherin seen during tumor progression. We used 3D, bioengineered human tissue constructs that mimic the complexity of their in vivo counterparts, to show that the tumor microenvironment can direct the re-expression of E-cadherin through the reversal of methylation-mediated silencing of its promoter. This loss of DNA methylation results from the induction of homotypic cell-cell interactions as cells undergo tissue organization. E-cadherin re-expression is associated with multiple epigenetic changes including altered methylation of a small number of CpGs, specific histone modifications, and control of miR-148a expression. These epigenetic changes may drive the plasticity of E-cadherin-mediated adhesion in different tissue microenvironments during tumor cell invasion and metastasis. Thus, we suggest that epigenetic regulation is a mechanism through which tumor cell colonization of metastatic sites occurs as E-cadherin-expressing cells arise from E-cadherin-deficient cells.
Mohamed Elsayed Deraz, Yasusei Kudo, Maki Yoshida, Mariko Obayashi, Takaaki Tsunematsu, Hirotaka Tani, M Samadarani B S Siriwardena, Reza Mohammad Keikhaee, Reza Mohammad Kiekhaee, Guangying Qi, Shinji Iizuka, Ikuko Ogawa, Giuseppina Campisi, Lorenzo Muzio Lo, Yoshimitsu Abiko, Akira Kikuchi and Takashi Takata : MMP-10/stromelysin-2 promotes invasion of head and neck cancer., PLoS ONE, Vol.6, No.10, 2011.
(Summary)
These results suggest that MMP-10 plays an important role in the invasion and metastasis of HNSCC, and that invasion driven by MMP-10 is partially associated with p38 MAPK inhibition. We suggest that MMP-10 can be used as a marker for prediction of metastasis in HNSCC.
Hiroko Hatano, Hideo Shigeishi, Yasusei Kudo, Koichiro Higashikawa, Kei Tobiume, Takashi Takata and Nobuyuki Kamata : Overexpression of receptor for hyaluronan-mediated motility (RHAMM) in MC3T3-E1 cells induces proliferation and differentiation through phosphorylation of ERK1/2., Journal of Bone and Mineral Metabolism, 2011.
(Summary)
Receptor for hyaluronan (HA)-mediated motility (RHAMM) was first described as a soluble HA binding protein released by sub-confluent migrating cells. We previously found that RHAMM was highly expressed and plays an important role in proliferation in the human cementifying fibroma (HCF) cell line, which we previously established. HCF is a benign fibro-osseous neoplasm of the jaw and is composed of fibrous tissue containing varying amounts of mineralized material. However, the pathogenesis of HCF is not clear. In this paper, we examined the roles of RHAMM in osteoblastic cells. We generated RHAMM-overexpressing MC3T3-E1 cells and examined the cell proliferation and differentiation of osteoblastic cells. In MC3T3-E1 cells, overexpressing RHAMM was located intracellular and activated ERK1/2. Interestingly, the ERK1/2 activated by RHAMM overexpression promoted cell proliferation and suppressed the differentiation of osteoblastic cells. Our findings strongly suggest that RHAMM may play a key role in the osteoblastic differentiation process. The rupture of balance from differentiation to proliferation induced by RHAMM overexpression may link to the pathogenesis of bone neoplasms such as HCF.
Sanae Uchida, Nobumoto Watanabe, Yasusei Kudo, Katsuji Yoshioka, Tsukasa Matsunaga, Yukihito Ishizaka, Hitoshi Nakagama, C Randy Y Poon and Katsumi Yamashita : SCF(TrCP) mediates stress-activated MAPK-induced Cdc25B degradation., Journal of Cell Science, Vol.124, No.Pt 16, 2816-2825, 2011.
(Summary)
Cdc25A, which is one of the three mammalian CDK-activating Cdc25 protein phosphatases (Cdc25A, B and C), is degraded through SCF(TrCP)-mediated ubiquitylation following genomic insult; however, the regulation of the stability of the other two Cdc25 proteins is not well understood. Previously, we showed that Cdc25B is primarily degraded by cellular stresses that activate stress-activated MAPKs, such as Jun NH(2)-terminal kinase (JNK) and p38. Here, we report that Cdc25B was ubiquitylated by SCF(TrCP) E3 ligase upon phosphorylation at two Ser residues in the TrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). Point mutation of these Ser residues to alanine (Ala) abolished the JNK-induced ubiquitylation by SCF(TrCP), and point mutation of DAG to AAG or DAA eradicated both TrCP binding and ubiquitylation. Further analysis of the mode of TrCP binding to this region revealed that the PEST-like sequence from E(82)SS to D(94)AG is crucially involved in both the TrCP binding and ubiquitylation of Cdc25B. Furthermore, the phospho-mimetic replacement of all 10 Ser residues in the E(82)SS to SPSP(104) region with Asp resulted in TrCP binding. Collectively, these results indicate that stress-induced Cdc25B ubiquitylation by SCF(TrCP) requires the phosphorylation of S(101)PS(103)P in the TrCP-binding-motif-like and adjacent PEST-like sequences.
(Keyword)
Animals / DNA Damage / Extracellular Signal-Regulated MAP Kinases / Humans / Mice / Mutagenesis, Site-Directed / Mutation / Phosphorylation / Protein Binding / Protein Engineering / Protein Interaction Domains and Motifs / Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Proteolysis / SKP Cullin F-Box Protein Ligases / Serine / Ubiquitination / cdc25 Phosphatases
Dan Xu, Fumitaka Takeshita, Yumiko Hino, Saori Fukunaga, Yasusei Kudo, Aya Tamaki, Junko Matsunaga, Ryou-U Takahashi, Takashi Takata, Akira Shimamoto, Takahiro Ochiya and Hidetoshi Tahara : miR-22 represses cancer progression by inducing cellular senescence., The Journal of Cell Biology, Vol.193, No.2, 409-424, 2011.
(Summary)
Cellular senescence acts as a barrier to cancer progression, and microRNAs (miRNAs) are thought to be potential senescence regulators. However, whether senescence-associated miRNAs (SA-miRNAs) contribute to tumor suppression remains unknown. Here, we report that miR-22, a novel SA-miRNA, has an impact on tumorigenesis. miR-22 is up-regulated in human senescent fibroblasts and epithelial cells but down-regulated in various cancer cell lines. miR-22 overexpression induces growth suppression and acquisition of a senescent phenotype in human normal and cancer cells. miR-22 knockdown in presenescent fibroblasts decreased cell size, and cells became more compact. miR-22-induced senescence also decreases cell motility and inhibits cell invasion in vitro. Synthetic miR-22 delivery suppresses tumor growth and metastasis in vivo by inducing cellular senescence in a mouse model of breast carcinoma. We confirmed that CDK6, SIRT1, and Sp1, genes involved in the senescence program, are direct targets of miR-22. Our study provides the first evidence that miR-22 restores the cellular senescence program in cancer cells and acts as a tumor suppressor.
Thao Phuong Nguyen, Yasusei Kudo, Maki Yoshida, Nobuyuki Kamata, Ikuko Ogawa and Takashi Takata : N-cadherin expression is involved in malignant behavior of head and neck cancer in relation to epithelial-mesenchymal transition., Histology and Histopathology, Vol.26, No.2, 147-156, 2011.
(Summary)
The loss of E-cadherin and the gain of N-cadherin expression are known as "cadherin switching". Cadherin switching is a major hallmark of epithelial-mesenchymal transition (EMT). EMT is a crucial process in cancer progression, providing cancer cells with the ability to escape from the primary focus, to invade stromal tissues and to migrate to distant regions. Although down-regulation of E-cadherin is well known in various cancers, there are a few studies on N-cadherin expression in cancer. Here, therefore, we investigated whether N-cadherin expression was associated with the progression of head and neck squamous cell carcinoma (HNSCC). First, we examined the expression of N-cadherin by immunohistochemistry and its correlation with clinico-pathological findings. High expression of N-cadherin was observed in 52 of 80 HNSCC cases and was significantly correlated with malignant behaviors. Next, we examined the correlation between N-cadherin and E-cadherin. Cadherin switching (high expression of N-cadherin and low expression of E-cadherin) was found in 30 of 80 HNSCC cases and was well correlated with histological differentiation, pattern of invasion and lymph node metastasis in HNSCC cases. Moreover, we examined the expression of N-cadherin and E-cadherin by RT-PCR in 16 HNSCC cell lines to confirm the immunohistochemical findings. N-cadherin expression was observed in 7 of 16 HNSCC cells, and cadherin switching was observed in 2 HNSCC cells. Interestingly, HNSCC cells with cadherin switching have EMT features. In conclusion, we suggest that i) N-cadherin may play an important role in malignant behaviors of HNSCC, and ii) cadherin switching might be considered as a discrete critical event in EMT and metastatic potential of HNSCC.
(Tokushima University Institutional Repository: 113585, PubMed: 21154228)
77.
Yasusei Kudo, Takaaki Tsunematsu and Takashi Takata : Oncogenic role of RUNX3 in head and neck cancer., Journal of Cellular Biochemistry, Vol.112, No.2, 387-393, 2011.
(Summary)
Cumulative evidences show that Runt-related transcription factor 3 (RUNX3) has a tumor suppressive role in various cancers. In particular, RUNX3 appears to be an important component of the transforming growth factor- (TGF-)-induced tumor suppression pathway. Contrary to reports on this tumor suppressive role of RUNX3, RUNX3 can also function as an oncogene when overexpressed. Recently, we found that RUNX3 overexpression was frequently observed and was well correlated with malignant behaviors in head and neck cancer, which is one of the most common types of human cancer. Moreover, it has been revealed that RUNX3 overexpression promoted cell growth and inhibited apoptosis in head and neck cancer cells. This review introduces the oncogenic role of RUNX3 in certain types of cancer including head and neck cancer.
(Keyword)
Animals / Core Binding Factor Alpha 3 Subunit / Head and Neck Neoplasms / Humans / Models, Biological
Shinji Iizuka, Yasusei Kudo, Maki Yoshida, Takaaki Tsunematsu, Yuji Yoshiko, Takashi Uchida, Ikuko Ogawa, Mutsumi Miyauchi and Takashi Takata : Ameloblastin regulates osteogenic differentiation by inhibiting Src kinase via cross talk between integrin beta1 and CD63., Molecular and Cellular Biology, Vol.31, No.4, 783-792, 2010.
(Summary)
Ameloblastin, the most abundant nonamelogenin enamel matrix protein, plays a role in ameloblast differentiation. Here, we found that ameloblastin was expressed in osteosarcoma cells; to explore the potential functions of ameloblastin in osteoblasts, we investigated whether this protein is involved in osteogenic differentiation and bone formation on the premise that CD63, a member of the transmembrane-4 glycoprotein superfamily, interacts with integrins in the presence of ameloblastin. Ameloblastin bound to CD63 and promoted CD63 binding to integrin 1. The interaction between CD63 and integrin 1 induced Src kinase inactivation via the binding of CD63 to Src. The reduction of Src activity and osteogenic differentiation mediated by ameloblastin were abrogated by treatment with anti-CD63 antibody and overexpression of constitutively active Src, respectively. Therefore, our results suggest that ameloblastin is expressed in osteoblasts and functions as a promoting factor for osteogenic differentiation via a novel pathway through the interaction between CD63 and integrin 1.
T Phuong Nguyen, Yasusei Kudo, Maki Yoshida, Shinji Iizuka, Ikuko Ogawa and Takashi Takata : N-cadherin expression is correlated with metastasis of spindle cell carcinoma of head and neck region., Journal of Oral Pathology & Medicine, Vol.40, No.1, 77-82, 2010.
(Summary)
Spindle cell carcinoma (SpCC) is a biphasic tumor composed of conventional squamous cell carcinoma and a malignant spindle cell component. SpCC expresses both epithelial and mesenchymal markers by immunohistochemical analysis. There is mounting evidence for sarcomatoid transformation from the epithelial component, supporting the theory that SpCC is a monoclonal neoplasm originating from a stem cell giving rise to both components. The loss of E-cadherin and the gain of N-cadherin expression are known as the "cadherin switching". Cadherin switching is a major hallmark of epithelial-mesenchymal transition (EMT). EMT is a crucial process in cancer progression providing cancer cells with the ability to escape from the primary focus, to invade stromal tissues, and to migrate to distant regions. Although E-cadherin down-regulation is well known in various cancers, there are a few studies on N-cadherin expression in cancer. Here, therefore, we investigated N-cadherin expression in the progression of head and neck SpCC. First, we examined cadherin switching in our established SpCC cell lines, SpCC-1 and SpCC-2. SpCC-1 and SpCC-2 cells were spindle in shape and showed cadherin switching. Moreover, we examined N-cadherin expression in 15 SpCC cases by immunohistochemistry. Although N-cadherin expression was not observed in non-neoplastic squamous epithelium, high expression of N-cadherin was observed in 10 of 15 SpCC cases. Interestingly, 6 of 7 SpCC cases with metastasis showed high expression of N-cadherin. In conclusion, our findings suggest that N-cadherin may play an important role in metastasis of SpCC in addition to the pathogenesis of SpCC of the head and neck.
(Keyword)
Adult / Aged / Aged, 80 and over / Cadherins / Carcinoma / Carcinoma, Squamous Cell / Cell Line, Tumor / Cell Transformation, Neoplastic / Clone Cells / Female / Head and Neck Neoplasms / Humans / Immunohistochemistry / Male / Middle Aged
Hiroko Hatano, Hideo Shigeishi, Yasusei Kudo, Koichiro Higashikawa, Kei Tobiume, Takashi Takata and Nobuyuki Kamata : RHAMM/ERK interaction induces proliferative activities of cementifying fibroma cells through a mechanism based on the CD44-EGFR., Laboratory Investigation; a Journal of Technical Methods and Pathology, Vol.91, No.3, 379-391, 2010.
(Summary)
We have previously established immortalized cells (HCF) from cementifying fibroma of the jaw bone. Here, we found that the receptor for hyaluronan (HA)-mediated motility (RHAMM) and epiregulin, a ligand for the epidermal growth factor receptor (EGFR), were highly expressed in HCF cells in comparison with osteoblasts by conducting a microarray analysis. The cell growth of HCF cells was significantly decreased by the knockdown of RHAMM using small interfering RNA (siRNA). RHAMM was associated with extracellular signal-regulated kinase (ERK) and essential for ERK phosphorylation. HCF cells had characteristic growth mechanisms in which epiregulin functions in an extracellular autocrine loop. Interestingly, exogenous HA induced the phosphorylation of EGFR, which was mainly dependent on CD44. The results raise the novel idea that the EGFR may activate Raf-MEK-ERK signaling in response to the binding of HA to CD44. Moreover, RHAMM was able to associate with TPX2 in the nucleus and was required for HA-induced activation of the Aurora A kinase. The results suggest that RHAMM has a predominant role in the cell cycle in HCF. Here, we report the new machinery by which RHAMM/ERK interaction induces the proliferative activity of cementifying fibroma cells via a specific signaling pathway through the CD44-EGFR axis.
Guangying Qi, Yasusei Kudo, Toshinori Ando, Takaaki Tsunematsu, Natsumi Shimizu, M Samadarani B S Siriwardena, Maki Yoshida, Reza Mohammad Keikhaee, Ikuko Ogawa and Takashi Takata : Nuclear Survivin expression is correlated with malignant behaviors of head and neck cancer together with Aurora-B., Oral Oncology, Vol.46, No.4, 263-270, 2010.
(Summary)
Survivin belongs to the inhibitors of apoptosis (IAP) gene family and inhibits apoptosis. Besides its role as IAP, Survivin recently appears to function as a subunit of the chromosomal passenger complex (CPC) for regulating cell division with other CPC proteins including Aurora-B and INCENP. Nuclear Survivin is suspected to control cell division, whereas cytoplasmic Survivin is considered cytoprotective. Although there are several studies on Survivin expression and its function as inhibition of apoptosis, there is no study on Survivin function as a CPC and its correlation with other CPC proteins in head and neck squamous cell carcinoma (HNSCC). Here, therefore, we examined nuclear Survivin expression and its functional correlation with Aurora-B in HNSCC. High expression of Survivin was well correlated with Aurora-B expression in nuclear fraction of HNSCC cell lines and tissues. Moreover, nuclear Survivin expression was significantly correlated with Ki-67 and Aurora-B expression by immunohistochemistry. Notably, HNSCC cases with nuclear Survivin and Aurora-B expression exhibited marked malignant behaviors. Interestingly, both Survivin and Aurora-B knockdown inhibited cell growth and tumorsphere formation. Overall suggest that nuclear Survivin may be involved in tumor progression together with Aurora-B, and that Survivin and Aurora-B can be useful diagnostic markers and therapeutic targets.
Masaaki Tatsuka, Sunao Sato, Akifumi Kanda, Tomoharu Miki, Nobuyuki Kamata, Shojiro Kitajima, Yasusei Kudo and Takashi Takata : Oncogenic role of nuclear accumulated Aurora-A., Molecular Carcinogenesis, Vol.48, No.9, 810-820, 2009.
(Summary)
Aurora-A, also known as Aik, BTAK, or STK15, is a centrosomal serine/threonine protein kinase, which is proto-oncogenic and is overexpressed in a wide range of human cancers. Besides gene amplification and mRNA overexpression, proteolytic resistance mechanisms are thought to contribute to overexpression of Aurora-A. However, it is not yet clear how overexpressed Aurora-A affects the expression of transformed phenotype. Here, we found that nuclear accumulation of Aurora-A was critical for transformation activity. Cellular protein fractionation experiments and immunoblot analysis demonstrated a predominance of Aurora-A in the nuclear soluble fraction in head and neck cancer cells. Indirect immunofluorescence using confocal laser microscopy confirmed nuclear Aurora-A in head and neck cancer cells, while most oral keratinocytes exhibited only centrosomal localization. The expression of nuclear export signal-fused Aurora-A demonstrated that the oncogenic transformation activity was lost on disruption of the nuclear localization. Thus, the cytoplasmic localization of overexpressed Aurora-A previously demonstrated by immunohistochemical analysis is not likely to correspond to that in intact cancer cells. This study identifies an alternative mode of Aurora-A overexpression in cancer, through nuclear rather than cytoplasmic functions. We suggest that substrates of Aurora-A in the cell nuclear soluble fraction can represent a novel therapeutic target for cancer.
(Keyword)
Animals / BALB 3T3 Cells / Cell Line / Cell Line, Tumor / Cell Nucleus / Cell Transformation, Neoplastic / Centrosome / Cytoplasm / Fluorescent Antibody Technique, Indirect / Green Fluorescent Proteins / HeLa Cells / Head and Neck Neoplasms / Humans / Immunoblotting / Immunoprecipitation / Keratinocytes / Mice / Microscopy, Confocal / Polymorphism, Single Nucleotide / Protein-Serine-Threonine Kinases / RNA, Small Interfering / Recombinant Fusion Proteins / Transfection
Takaaki Tsunematsu, Yasusei Kudo, Shinji Iizuka, Ikuko Ogawa, Tsuyoshi Fujita, Hidemi Kurihara, Yoshimitsu Abiko and Takashi Takata : RUNX3 has an oncogenic role in head and neck cancer., PLoS ONE, Vol.4, No.6, e5892, 2009.
(Summary)
Our findings suggest that i) RUNX3 has an oncogenic role in HNSCC, ii) RUNX3 expression observed in HNSCC may be caused in part by demethylation during cancer development, and iii) RUNX3 expression can be a useful marker for predicting malignant behavior and the effect of chemotherapeutic drugs in HNSCC.
Hiroko Hatano, Yasusei Kudo, Ikuko Ogawa, Takaaki Tsunematsu, Akira Kikuchi, Yoshimitsu Abiko and Takashi Takata : IFN-induced transmembrane protein 1 promotes invasion at early stage of head and neck cancer progression., Clinical Cancer Research, Vol.14, No.19, 6097-6105, 2008.
(Summary)
Our findings suggest that IFITM1 plays an important role for the invasion at the early stage of HNSCC progression and that IFITM1 can be a therapeutic target for HNSCC.
S B S M Siriwardena, Yasusei Kudo, I Ogawa, M W Tilakaratne and Takashi Takata : Aberrant beta-catenin expression and adenomatous polyposis coli gene mutation in ameloblastoma and odontogenic carcinoma., Oral Oncology, Vol.45, No.2, 103-108, 2008.
(Summary)
The Wnt pathway is involved in carcinogenesis and three regulatory genes of the Wnt pathway, APC (adenomatous polyposis coli), beta-catenin and Axin are frequently mutated in some primary human cancers. This study was conducted to clarify the relation of beta-catenin accumulation and the mutation of the CTNNB1 (beta-catenin) gene with the mutation of APC gene in the process of development of odontogenic tumors including ameloblastoma and odontogenic carcinoma (OC). beta-Catenin accumulation was examined by immunohistochemistry in formalin-fixed, paraffin-embedded samples of six ameloblastomas and eight OCs. We also performed a mutation analysis of CTNNB1 and APC to examine the cause of beta-catenin accumulation. All ameloblastoma cases and six out of eight (75%) OC cases exhibited beta-catenin accumulation in the nucleus. CTNNB1 mutation was only found in one OC case, whereas three of six (50%) ameloblastoma cases and two out of eight (25%) OC cases had APC mutations within the mutational cluster region. Our findings suggest that aberrant beta-catenin expression and APC missense mutation may play an important role for the pathogenesis of epithelial odontogenic tumors.
Eiji Tanaka, B Emanuel Rego, Yasunori Iwabuchi, Toshihiro Inubushi, Harm Jan Koolstra, J Eijden Theo M G van, Nobuhiko Kawai, Yasusei Kudo, Takashi Takata and Kazuo Tanne : Biomechanical response of condylar cartilage-on-bone to dynamic shear., Journal of Biomedical Materials Research. Part A, Vol.85, No.1, 127-132, 2008.
(Summary)
Shear stress can result in fatigue, damage, and irreversible deformation of the mandibular condylar cartilage. However, little information is available on its dynamic properties in shear. We tested the hypothesis that the dynamic shear properties of the condylar cartilage depend on the frequency and amplitude of shear strain. Ten porcine mandibular condyles were used for dynamic shear tests. Two cartilage-bone plugs were dissected from each condyle and tested in a simple shear sandwich configuration under a compressive strain of 10%. Sinusoidal shear strain was applied with an amplitude of 1.0, 2.0, and 3.0% and a frequency range between 0.01 and 10 Hz. The magnitudes of the shear dynamic moduli were found to be dependent on the frequency and the shear strain amplitude. They increased with shear strain. tan delta ranged from 0.2 to 0.4, which means that the cartilage is primarily elastic in nature and has a small but not negligible viscosity. In conclusion, the present results show that the shear behavior of the mandibular condylar cartilage is dependent on the frequency and amplitude of the applied shear strain. The observed shear characteristics suggest a significant role of shear strain on the interstitial fluid flow within the cartilage.
(Keyword)
Animals / biomechanics / Bone and Bones / Cartilage / Mandibular Condyle / Shear Strength / Stress, Mechanical / Swine
Sunao Sato, Masae Kitagawa, Kiyako Sakamoto, Shinji Iizuka, Yasusei Kudo, Ikuko Ogawa, Mutsumi Miyauchi, Y Emily Chu, L Brian Foster, J Martha Somerman and Takashi Takata : Enamel matrix derivative exhibits anti-inflammatory properties in monocytes., Journal of Periodontology, Vol.79, No.3, 535-540, 2008.
(Summary)
In addition to EMD's published role in inducing proliferation, migration, adhesion, mineralization, and differentiation of periodontal ligament cells, our results indicated that EMD modulates two inflammation-associated factors, TNF-alpha and PGE(2), in monocytes.
Shojiro Kitajima, Yasusei Kudo, Ikuko Ogawa, Masaaki Tatsuka, Hidehiko Kawai, Michele Pagano and Takashi Takata : Constitutive phosphorylation of aurora-a on ser51 induces its stabilization and consequent overexpression in cancer., PLoS ONE, Vol.2, No.9, e944, 2007.
(Summary)
The serine/threonine kinase Aurora-A (Aur-A) is a proto-oncoprotein overexpressed in a wide range of human cancers. Overexpression of Aur-A is thought to be caused by gene amplification or mRNA overexpression. However, recent evidence revealed that the discrepancies between amplification of Aur-A and overexpression rates of Aur-A mRNA were observed in breast cancer, gastric cancer, hepatocellular carcinoma, and ovarian cancer. We found that aggressive head and neck cancers exhibited overexpression and stabilization of Aur-A protein without gene amplification or mRNA overexpression. Here we tested the hypothesis that aberration of the protein destruction system induces accumulation and consequently overexpression of Aur-A in cancer. Aur-A protein was ubiquitinylated by APC(Cdh1) and consequently degraded when cells exited mitosis, and phosphorylation of Aur-A on Ser51 was observed during mitosis. Phosphorylation of Aur-A on Ser51 inhibited its APC(Cdh1)-mediated ubiquitylation and consequent degradation. Interestingly, constitutive phosphorylation on Ser51 was observed in head and neck cancer cells with protein overexpression and stabilization. Indeed, phosphorylation on Ser51 was observed in head and neck cancer tissues with Aur-A protein overexpression. Moreover, an Aur-A Ser51 phospho-mimetic mutant displayed stabilization of protein during cell cycle progression and enhanced ability to cell transformation. Broadly, this study identifies a new mode of Aur-A overexpression in cancer through phosphorylation-dependent inhibition of its proteolysis in addition to gene amplification and mRNA overexpression. We suggest that the inhibition of Aur-A phosphorylation can represent a novel way to decrease Aur-A levels in cancer therapy.
Masae Kitagawa, Ikuko Ogawa, Kaori Shima, Sadamitsu Hashimoto, Yasusei Kudo, Mutsumi Miyauchi, Hidetoshi Tahara, Masaki Shimono and Takashi Takata : Immortalization and characterization of pleomorphic adenoma cells by transfection with the hTERT gene., International Journal of Oncology, Vol.31, No.2, 339-344, 2007.
(Summary)
Pleomorphic adenomas (PAs) of salivary glands are characterized by the mixed appearance of epithelial and mesenchymal-like components such as myxoid and chondroid tissues. Although various studies have examined PAs, thus far it is not clear how PAs make these multiple components. Thus, clarification of the histodifferentiation of this unique salivary gland tumor using not only tissues in vivo but also PA cells cultured in vitro is necessary. However, no in vitro model of PA has been reported, because normal and benign tumor cells tend to grow slowly and senesce quickly in culture. Therefore, we immortalized cells using transfection of the hTERT gene without otherwise altering the nature of those cells. The immortalized PA cells expressed mRNA of the pleomorphic adenoma gene 1 and showed epithelial and neoplastic myoepithelial characteristics by immunohistochemical immunofluorescence analyses and ultrastructural study. Our findings suggest that these cells will be a useful model to study the cellular differentiation of PA.
S B S M Siriwardena, A Tilakaratne, D E A P Amaratunga, K M N G P Udagama, Ikuko Ogawa, Yasusei Kudo, Takashi Takata and M W Tilakaratne : Analysis of histopathological and immunohistochemical differences of oral squamous cell carcinoma in young and old patients in Sri Lanka., Journal of Oral Pathology & Medicine, Vol.36, No.6, 357-362, 2007.
(Summary)
Although tumours of the young patients showed more nuclear aberrations, OSCC of the older patients is proliferative and showed higher metastatic rate.
(Keyword)
Adult / Age Factors / Carcinoma, Squamous Cell / Chi-Square Distribution / Humans / Lymphatic Metastasis / Middle Aged / Mitosis / Mouth Neoplasms / Proliferating Cell Nuclear Antigen / Sri Lanka / Tumor Suppressor Protein p53
Reza Mohammad Keikhaee, Yasusei Kudo, Samadarani Siriwardena, Lanyan Wu, Ikuko Ogawa and Takashi Takata : Skp2 expression is associated with down-regulation of p27 protein and cell proliferation in salivary adenoid cystic carcinoma., Virchows Archiv, Vol.450, No.5, 567-574, 2007.
(Summary)
Adenoid cystic carcinoma (ACC) is a malignant salivary gland tumor, which shows frequent recurrence and metastasis, ultimately with a poor outcome. We previously demonstrated that p27 down-regulation is frequently found and is due to an enhancement of its degradation in ACC. In this study, we transfected nondegradable p27 mutant (T187A) and wild-type gene into ACC cell line. Transfection of T187A mutant gene was more effective on inhibition of cell growth of ACC cells, suggesting that aberration of p27 degradation may be present in ACC. As F-box protein S-phase kinase-associated protein 2 (Skp2), which is necessary for ubiquitin-mediated degradation of p27, is involved in p27 down-regulation in various cancers, we examined the Skp2 expression and its association with p27 expression in 50 ACC cases. We found Skp2 expression in 36% of ACC cases and inverse association between the expression of Skp2 and p27. Moreover, Skp2 small interfering ribonucleic acid (siRNA) transfection decreased Skp2 protein and accumulation of p27 protein and inhibited the cell growth of ACC cells in vitro. These findings, overall, suggest that Skp2 may play an important role in ACC development through the down-regulation of p27 and that Skp2 siRNA can be a novel modality of cancer gene therapy for suppression of p27 down-regulation in ACC.
Masae Kitagawa, Hirota Ueda, Sinji Iizuka, Kiyako Sakamoto, Hiroko Oka, Yasusei Kudo, Ikuko Ogawa, Mutsumi Miyauchi, Hidetoshi Tahara and Takashi Takata : Immortalization and characterization of human dental pulp cells with odontoblastic differentiation., Archives of Oral Biology, Vol.52, No.8, 727-731, 2007.
(Summary)
We were able to establish a cell line of immortalized human dental pulp cells with odontoblastic differentiation which will be a useful cell model for studying the mechanism of proliferation and differentiation of odontoblasts.
S B S M Siriwardena, Yasusei Kudo, I Ogawa, K M N G P Udagama, M W Tilakaratne and Takashi Takata : VEGF-C is associated with lymphatic status and invasion in oral cancer., Journal of Clinical Pathology, Vol.61, No.1, 103-108, 2007.
(Summary)
Results suggest that VEGF-C may play an important role for lymphangiogenesis and invasion in the metastatic process and can be a strong predicting factor for metastasis of OSCC.
Guangying Qi, Ikuko Ogawa, Yasusei Kudo, Mutsumi Miyauchi, S B S M Siriwardena, Fumio Shimamoto, Masaaki Tatsuka and Takashi Takata : Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer., Virchows Archiv, Vol.450, No.3, 297-302, 2007.
(Summary)
Aurora-B kinase is a chromosomal passenger protein and is essential for chromosome segregation and cytokinesis. Aurora-B overexpression in various cancer cells induces chromosomal number instability to produce multinuclearity and relates to metastasis. Here, we examined the expression of Aurora-B in oral squamous cell carcinoma (OSCC) to elucidate the relationship between Aurora-B expression and clinico-pathological findings by immunohistochemistry. Aurora-B expression was observed in normal oral squamous epithelia and OSCC cases, but the number of positive cells was significantly higher in OSCC than in normal squamous epithelium (p < 0.01). The labeling index of Aurora-B was significantly correlated with lymph node metastasis (p < 0.01) and histological grades of differentiation (p < 0.01). We also compared Aurora-B expression with Ki-67 expression and a positive correlation was found (p < 0.0001). Moreover, Aurora-B expression is significantly more frequent in multinuclear tumor cells than in total tumor cells. In summary, we found that Aurora-B expression was well correlated with cell proliferation, induction of multinuclear cells, histological differentiation, and metastasis in OSCC. These findings suggest that Aurora-B may be involved in tumor progression and that Aurora-B can be a new diagnostic and therapeutic target for OSCC.
S B S M Siriwardena, Yasusei Kudo, I Ogawa, M Kitagawa, S Kitajima, H Hatano, M W Tilakaratne, Mutsumi Miyauchi and Takashi Takata : Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer., British Journal of Cancer, Vol.95, No.10, 1396-1403, 2006.
(Summary)
Oral squamous-cell carcinoma (OSCC) is one of the most common types of human cancer. Typically OSCC cells show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. We previously identified Periostin as the gene demonstrating the highest fold change expression in the invasive clone by comparing the transcriptional profile of parent OSCC cell line and a highly invasive clone. Here, we demonstrated that Periostin overexpression enhanced invasiveness in oral cancer cell lines. To know the role of Periostin in invasion, angiogenesis and metastasis in OSCC cases, we first examined the expression of Periostin mRNA in 31 OSCC cases by RT-PCR and Periostin protein in 74 OSCC cases by immunohistochemistry. Then, we compared the Periostin expression with invasion pattern, metastasis and blood vessel density. Periostin mRNA and protein overexpression were frequently found in OSCC cases and Periostin expression was well correlated with the invasion pattern and metastasis. Moreover, blood vessel density of Periostin-positive cases was higher than those of Periostin-negative cases. Interestingly, recombinant Periostin enhanced capillary formation in vitro in a concentration-dependant manner. In summary, these findings suggest that Periostin may promote invasion and angiogenesis in OSCC, and that Periostin can be a strong marker for prediction of metastasis in oral cancer patients.
Masae Kitagawa, Yasusei Kudo, Shinji Iizuka, Ikuko Ogawa, Yoshimitsu Abiko, Mutsumi Miyauchi and Takashi Takata : Effect of F-spondin on cementoblastic differentiation of human periodontal ligament cells., Biochemical and Biophysical Research Communications, Vol.349, No.3, 1050-1056, 2006.
(Summary)
Cementum is a mineralized tissue produced by cementoblasts covering the roots of teeth that provides for the attachment of periodontal ligament to roots and surrounding alveolar bone. To study the mechanism of proliferation and differentiation of cementoblasts is important for understanding periodontal physiology and pathology including periodontal tissue regeneration. However, the detailed mechanism of the proliferation and differentiation of human cementoblasts is still unclear. We previously established human cementoblast-like (HCEM) cell lines. We thought that comparing the transcriptional profiles of HCEM cells and human periodontal ligament (HPL) cells derived from the same teeth could be a good approach to identify genes that influence the nature of cementoblasts. We identified F-spondin as the gene demonstrating the high fold change expression in HCEM cells. Interestingly, F-spondin highly expressing HPL cells showed similar phenotype of cementoblasts, such as up-regulation of mineralized-related genes. Overall, we identified F-spondin as a promoting factor for cementoblastic differentiation.
Yasusei Kudo, Ikuko Ogawa, Masae Kitagawa, Shojiro Kitajima, M Siriwardena B S Samadarani, Noriko Aobara, Chika Matsuda, Mutsumi Miyauchi and Takashi Takata : Establishment and characterization of a spindle cell squamous carcinoma cell line., Journal of Oral Pathology & Medicine, Vol.35, No.8, 479-483, 2006.
(Summary)
In the present study, we newly established a SCSC cell line with strong invasiveness. This is the first report on the establishment of SCSC cell line. The SCSC cell line can be a useful cell model for the study to know the cytodifferentiation and nature of SCSC.
Masae Kitagawa, Hidetoshi Tahara, Shoji Kitagawa, Hiroko Oka, Yasusei Kudo, Sunao Sato, Ikuko Ogawa, Mutsumi Miyaichi and Takashi Takata : Characterization of established cementoblast-like cell lines from human cementum-lining cells in vitro and in vivo., Bone, Vol.39, No.5, 1035-1042, 2006.
(Summary)
To study cellular characteristics of human cementoblasts using a cellular model is important for understanding the mechanisms of homeostasis and regeneration of periodontal tissues. However, at present no immortalized human cementoblast cell line has been established due to limitation of the life span. In the present study, therefore, we attempted to establish human cementoblast-like cell lines by transfection with telomerase catalytic subunit hTERT gene. Two stable clones (HCEM-1 and -2) with high telomerase activity were obtained and they grew over 200 population doublings without significant growth retardation. The expression of mRNA for differentiation markers, type I collagen, alkaline phosphatase (ALP), runt-related transcription factor 2, osteocalcin, bone sialoprotein and cementum-derived protein was revealed in these clones by RT-PCR. Moreover, these cells showed high ALP activity and calcified nodule formation in vitro. Interestingly, HCEM-2 showed cementum like formation on the surface of hydroxyapatites granules by subcutaneous transplantation into immunodeficient mice with hydroxyapatite granules. Thus, we established human cementoblast-like cell lines. We suggest that HCEM cell lines can be useful cell models for investigating the characteristics of human cementoblasts.
Yasusei Kudo, Ikuko Ogawa, Shojiro Kitajima, Masae Kitagawa, Hidehiko Kawai, M Patrick Gaffney, Mutsumi Miyauchi and Takashi Takata : Periostin promotes invasion and anchorage-independent growth in the metastatic process of head and neck cancer., Cancer Research, Vol.66, No.14, 6928-6935, 2006.
(Summary)
Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer. Typically, HNSCC cells show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. However, molecular mechanisms associated with the invasion and metastasis of HNSCC remain poorly understood. Here, we identified periostin as an invasion-promoting factor in HNSCC by comparing the gene expression profiles between parent HNSCC cells and a highly invasive clone. Indeed, periostin overexpression promoted invasion and anchorage-independent growth both in vitro and in vivo in HNSCC cells. Moreover, periostin-overexpressing cells spontaneously metastasized to cervical lymph nodes and to the lung through their aggressive invasiveness in an orthotopic mouse model of HNSCC. Interestingly, periostin was highly expressed in HNSCCs in comparison with normal tissues, and the level of periostin expression was well correlated with the invasiveness of HNSCC cases. In summary, these findings suggest that periostin plays an important role in the invasion and anchorage-independent growth of HNSCC.
Masae Kitagawa, Shoji Kitagawa, Yasusei Kudo, Ikuko Ogawa, Mutsumi Miyauchi, Hidetoshi Tahara, Toshinori Ide and Takashi Takata : Establishment of cementoblast cell lines from rat cementum lining cells by transfection with temperature-sensitive simian virus-40 T-antigen gene., Bone, Vol.37, No.2, 220-226, 2005.
(Summary)
Defining the regulatory mechanisms promoting differentiation and proliferation of cementoblasts has not been well understood, because of the lack of cell models in vitro. To establish an in vitro cell model for the cementoblasts, extracted rat molars obtained from 8-week-old rats were used. Cells lining the root surface (cemetoblasts) were obtained by an enzymatic digestion method, and immediately immortalized by transfection of thermolabile SV40 T-antigen gene. The transfected cementum lining cell clones, RCM-C3 and -C4, were maintained for more than 200 population doublings (PD), while the original cells stopped their growth at 60 PD. Thus, immortalized cell lines decreased expression of SV40 T-antigen and subsequently cell proliferation at non-permissive temperature (39 degrees C). Reverse-transcribed-polymerase chain reaction indicated expression of gene for type I collagen, alkaline phosphatase (ALP), osteopontin, and osteocalcin mRNA at both permissive (33 degrees C) and non-permissive (39 degrees C) temperatures. RCM-C4 expressed higher bone siaploprotein (BSP) mRNA than RCM-C3, and further RCM-C4 showed higher BSP mRNA at 39 degrees C than 33 degrees C. High ALP activity and mineralized nodule formation were observed at 39 degrees C in both cell lines. These findings suggested that the cell lines, RCM-C3 and -C4, are useful model for studying the regulatory mechanisms of differentiation and proliferation of cementoblasts.
Yasusei Kudo, Shojiro Kitajima, Ikuko Ogawa, Masae Kitagawa, Mutsumi Miyauchi and Takashi Takata : Small interfering RNA targeting of S phase kinase-interacting protein 2 inhibits cell growth of oral cancer cells by inhibiting p27 degradation., Molecular Cancer Therapeutics, Vol.4, No.3, 471-476, 2005.
(Summary)
S phase kinase-interacting protein 2 (Skp2), an F box protein, is required for the ubiquitination and consequent degradation of p27. It is well known that reduced expression of p27 is frequently observed in various cancers including oral squamous cell carcinoma and is due to an enhancement of its protein degradation. Our previous study showed that overexpression of Skp2 was frequently found in oral squamous cell carcinoma and inversely correlated with p27 expression. Recently, a technique known as RNA interference has been successfully adapted to mammalian cells. In the present study, we investigated if small interfering RNA (siRNA)-mediated gene silencing of Skp2 can be employed in order to inhibit p27 down-regulation in oral squamous cell carcinoma. We used a siRNA plasmid vector, which has an advantage over synthetic siRNAs in determining the effects of decreasing the high constitutive levels of Skp2 protein in oral squamous cell carcinoma. We showed that Skp2 siRNA transfection decreased Skp2 protein and induced the accumulation of p27 protein in oral squamous cell carcinoma cells. Moreover, p27 protein in Skp2 siRNA-transfected cells is more stabilized than that in control siRNA-transfected cells. Interestingly, Skp2 siRNA inhibited the cell proliferation of oral squamous cell carcinoma cells both in vitro and in vivo. Our findings suggest that siRNA-mediated gene silencing of Skp2 can be a novel modality of cancer gene therapy for suppression of p27 down-regulation.
Yasusei Kudo, Shojiro Kitajima, Ikuko Ogawa, Mutsumi Miyauchi and Takashi Takata : Down-regulation of Cdk inhibitor p27 in oral squamous cell carcinoma., Oral Oncology, Vol.41, No.2, 105-116, 2005.
(Summary)
Oral squamous cell carcinoma (OSCC) is the most frequent malignant neoplasm of the head and neck region. Conversion of normal cells to cancer cells is achieved through a multi-step process that is closely associated with the accumulation of multiple gene changes including both oncogenes and tumour suppressor genes. The proliferation and progression of cancer may be caused by abnormalities of various positive and negative cell cycle regulators. Cell cycle progression is positively regulated by multiple cyclins and cyclin-dependent kinases (Cdks) and cyclin/Cdk complexes are negatively regulated by a number of Cdk inhibitors including p27. p27 is a Cdk inhibitor and plays an important role in negative regulation of the cell cycle during G0 and G1 phases. Degradation of p27 is a critical event for the G1/S transition and occurs through ubiquitination by SCF(Skp2) and subsequent degradation by the 26S proteasome. It has been revealed that down-regulation of p27 is frequently found in various cancers, including OSCC, and is due to an enhancement of its degradation. Importantly, down-regulation of p27 is well associated with its malignancy including poor prognosis in various cancers. Moreover, aggressive human cancers express low levels of p27 because of its decreased stability. More recent evidence suggests that Skp2 and Cks1, the specific recognition factors for p27 ubiquitination, have oncogenic properties. This review will focus on down-regulation of p27 and mechanism of its down-regulation in OSCC.
Shojiro Kitajima, Yasusei Kudo, Ikuko Ogawa, Tarig Bashir, Masae Kitagawa, Mutsumi Miyauchi, Michele Pagano and Takashi Takata : Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation., The American Journal of Pathology, Vol.165, No.6, 2147-2155, 2004.
(Summary)
Down-regulation of p27 is frequently observed in various cancers due to an enhancement of its degradation. Skp2 is required for the ubiquitination and consequent degradation of p27 protein. Another protein called Cks1 is also required for p27 ubiquitination in the SCF(Skp2) ubiquitinating machinery. In the present study, we examined Cks1 expression and its correlation with p27 in oral squamous cell carcinoma (OSCC) derived from tongue and gingiva. By immunohistochemical analysis, high expression of Cks1 was present in 62% of OSCCs in comparison with 0% of normal mucosae. In addition, 65% of samples with low p27 expression displayed high Cks1 levels. Finally, Cks1 expression was well correlated with Skp2 expression and poor prognosis. To study the role of Cks1 overexpression in p27 down-regulation, we transfected Cks1 with or without Skp2 into OSCC cells. Cks1 transfection could not induce a p27 down-regulation by itself, but both Cks1 and Skp2 transfection strongly induced. Moreover, we inhibited Cks1 expression by small interference RNA (siRNA) in OSCC. Cks1 siRNA transfection induced p27 accumulation and inhibited the growth of OSCC cells. These findings suggest that Cks1 overexpression may play an important role for OSCC development through Skp2-mediated p27 degradation, and that Cks1 siRNA can be a novel modality of gene therapy.
Yasusei Kudo, Daniele Guardavaccaro, G Patricia Santamaria, Ryo Koyama-Nasu, Esther Latres, Roderick Bronson, Lili Yamasaki and Michele Pagano : Role of F-box protein betaTrcp1 in mammary gland development and tumorigenesis., Molecular and Cellular Biology, Vol.24, No.18, 8184-8194, 2004.
(Summary)
The F-box protein betaTrcp1 controls the stability of several crucial regulators of proliferation and apoptosis, including certain inhibitors of the NF-kappaB family of transcription factors. Here we show that mammary glands of betaTrcp1(-/-) female mice display a hypoplastic phenotype, whereas no effects on cell proliferation are observed in other somatic cells. To investigate further the role of betaTrcp1 in mammary gland development, we generated transgenic mice expressing human betaTrcp1 targeted to epithelial cells under the control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. Compared to controls, MMTV betaTrcp1 mammary glands display an increase in lateral ductal branching and extensive arrays of alveolus-like protuberances. The mammary epithelia of MMTV betaTrcp1 mice proliferate more and show increased NF-kappaB DNA binding activity and higher levels of nuclear NF-kappaB p65/RelA. In addition, 38% of transgenic mice develop tumors, including mammary, ovarian, and uterine carcinomas. The targeting of betaTrcp1 to lymphoid organs produces no effects on these tissues. In summary, our results support the notion that betaTrcp1 positively controls the proliferation of breast epithelium and indicate that alteration of betaTrcp1 function and expression may contribute to malignant behavior of breast tumors, at least in part through NF-kappaB transactivation.
Mutsumi Miyauchi, M Hiraoka, H Oka, S Sato, Yasusei Kudo, I Ogawa, K Noguchi, I Ishikawa and Takashi Takata : Immuno-localization of COX-1 and COX-2 in the rat molar periodontal tissue after topical application of lipopolysaccharide., Archives of Oral Biology, Vol.49, No.9, 739-746, 2004.
(Summary)
Up-regulation of prostaglandin E2 (PGE2) production in the periodontal tissue is considered to be important for periodontal tissue destruction. The purpose of the study was to demonstrate the dynamic changes of immuno-localization of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in rat periodontal tissue after topical application of lipopolysaccharide (LPS: 5 mg/ml in physiological saline) from Escherichia coli into the rat molar gingival sulcus. In the normal periodontal tissue, small numbers of junctional epithelium (JE) cells and numerous osteocytes embedded in alveolar bone constitutively expressed COX-1. The COX-1 expression was not effected by LPS application. JE cells, especially in the coronal portion of JE also expressed COX-2. LPS application induced the JE cells with consequent transient expression of COX-2 with a peak at day 1. These findings suggest that JE cells may play a critical role in first defense line against LPS challenge and PGE2 from JE cells may be responsible for the initiation of periodontal inflammation. In the deep periodontal tissue, cementoblasts and osteoblasts showed constitutive expression of COX-2, which may be induced by continuous cyclic tension force due to occlusal pressure. LPS application caused a transient up-regulation of COX-2 expression in periodontal ligament fibroblasts, cementoblasts and osteoblasts. It is suggested that the inducible production of PGE2 via COX-2 by these cells may be associated with connective tissue destruction and alveolar bone resorption.
Yasusei Kudo, Shojiro Kitajima, Ikuko Ogawa, Masae Hiraoka, Soodabeh Sargolzaei, Reza Mohammad Keikhaee, Sunao Sato, Mutsumi Miyauchi and Takashi Takata : Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beta-catenin., Clinical Cancer Research, Vol.10, No.16, 5455-5463, 2004.
(Summary)
The extent of lymph node metastasis is a major determinant in the prognosis of oral squamous cell carcinoma (OSCC). Abnormalities of cell adhesion molecules are known to play an important role in invasion and metastasis of cancer cells through the loss of cell-to-cell adhesion. In this study, we isolated highly invasive clones from an OSCC cell line established from a lymph node metastasis by using an in vitro invasion assay method and compared the abnormalities of cell adhesion molecule E-cadherin and beta-catenin in these cells. The isolated, highly invasive clones showed significant invasive capacity and reduction of E-cadherin and membranous beta-catenin protein in comparison with parent cells. We found that reduced expression of E-cadherin was due to methylation of its promoter region. In fact, most invasive and metastatic area of OSCCs showed reduced expression and methylation of E-cadherin. Moreover, we found that reduced expression of membranous beta-catenin was due to its protein degradation. Reduced expression of membranous beta-catenin was also found frequently in invasive and metastatic areas of OSCCs. In summary, invasion and metastasis of OSCC cells require methylation of E-cadherin and/or degradation of membranous beta-catenin. In addition, we suggest that the method of isolation of highly invasive clones may be useful for studies aimed at discovering novel genes involved in invasion and metastasis.
Mutsumi Miyauchi, Shoji Kitagawa, Masae Hiraoka, Akihisa Saito, Sunao Sato, Yasusei Kudo, Ikuko Ogawa and Takashi Takata : Immunolocalization of CXC chemokine and recruitment of polymorphonuclear leukocytes in the rat molar periodontal tissue after topical application of lipopolysaccharide., Histochemistry and Cell Biology, Vol.121, No.4, 291-297, 2004.
(Summary)
This study investigated the recruitment of polymorphonuclear leukocytes (PMNs) and the immunolocalization of CXC chemokines, including macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant-2 (CINC-2) in rat periodontal tissue after topical application of lipopolysaccharide (LPS; 5 mg/ml) from Escherichia coli into the rat molar gingival sulcus. In normal periodontal tissues, a small number of MIP-2- and CINC-2-positive cells were seen in junctional epithelium (JE), especially in its coronal half. After topical application of LPS, a prominent increase of MIP-2- and CINC-2-positive JE cells was observed. Almost all JE cells strongly expressed them at day 1 and day 2, and then the number of chemokine-positive cells returned to normal at day 7. Corresponding to these chemokine expressions, LPS application induced a significant increase in the number of PMNs in the sub-JE area from 1 h to 2 days and a significant increase in JE area from 3 h to 5 days, indicating a dynamic flow of PMNs from the sub-JE area into JE. These findings indicated that JE cells produced MIP-2 and CINC-2 in response to LPS stimulation and suggested that MIP-2 and CINC-2 may be responsible for PMN migration toward the periodontal pathogen and may play an important role in the initiation of inflammation and subsequent periodontal tissue destruction.
Overall, these findings suggest that the inhibition of the invasive potential by upregulation of CD44v9 expression may be due to enhanced cell-cell adhesion. In our opinion, the upregulation of CD44v9 may be a target for future cancer treatment.
L Muzio Lo, G Pannone, R Leonardi, S Staibano, D M Mignogna, G Rosa De, Yasusei Kudo, Takashi Takata and C D Altieri : Survivin, a potential early predictor of tumor progression in the oral mucosa., Journal of Dental Research, Vol.82, No.11, 923-928, 2003.
(Summary)
Survivin is a recently described apoptosis inhibitor selectively over-expressed in most tumors. Immunohistochemistry was used to investigate a potential role of survivin as an early predictor of malignant transformation in precancerous and cancerous lesions of the oral cavity. Survivin was present in 10/30 cases (33%) of oral precancerous lesions without malignant progression, and in 15/16 cases (94%) of oral precancerous lesions evolved into full-blown squamous cell carcinoma. Tumors that progressed from these precancerous lesions retained widespread survivin positivity (100%). Variations among group means were highly statistically significant (p < 0.001). No significant correlation was found between survivin expression and the degree of dysplasia. High expression of cytoplasmic/nuclear survivin is an early event during oral carcinogenesis and may provide a useful tool for the identification of precancerous lesions at higher risk of progression into invasive carcinoma.
Yasusei Kudo, Shojiro Kitajjma, Sunao Sato, Mutsumi Miyauchi, Ikuko Ogawa and Takashi Takata : Establishment of an oral squamous cell carcinoma cell line with high invasive and p27 degradation activities from a lymph node metastasis., Oral Oncology, Vol.39, No.5, 515-520, 2003.
(Summary)
The extent of lymph node metastasis is a major determinant in the prognosis of oral squamous cell carcinoma (OSCC). We present here a new OSCC cell line, MSCC-1, established from a lymph node metastasis of a patient with OSCC of gingiva. First, we examined the expression of p27, p53 and Ki-67 in non-neoplastic mucosa, primary and metastatic cancer lesions by immunohistochemistry. Metastatic cancer cells in the lymph node showed the reduced expression of p27 in comparison with cancer cells in the primary lesion. Cancer celLs both in the primary and metastatic lesions showed overexpression of p53 and Ki-67. Overexpression of p53 and reduced expression of p27 in MSCC-1 cells were also determined by western blot analysis. To characterize MSCC-1 cells, furthermore, we examined the invasive activity and cell proliferation of MSCC-1, comparing with those of other OSCC cell lines, HSC-2 and HSC-3 cells. The invasive capacity of MSCC-1 cells was significant higher than HSC-2 and HSC-3 cells, but cell growth of MSCC-1 cells was slower than HSC-2 and HSC-3 cells. Moreover, we examined the p27 degradation activity by in vitro degradation assay. Interestingly, MSCC-1 cells have the strongest p27 degradation activity among the OSCC cell lines examined. In the present study, we newly established MSCC-1 cells with strong invasiveness and p27 degradation activity from a metastatic lesion. These findings suggest that high activity of p27 degradation may concern with invasiveness of OSCC cells and that MSCC-1 cells can be a useful cell model for studying the detailed mechanism of p27 degradation, invasion and metastasis of OSCC.
Daniele Guardavaccaro, Yasusei Kudo, Jérôme Boulaire, Marco Barchi, Luca Busino, Maddalena Donzelli, Florence Margottin-Goguet, K Peter Jackson, Lili Yamasaki and Michele Pagano : Control of meiotic and mitotic progression by the F box protein β-Trcp1 in vivo., Developmental Cell, Vol.4, No.6, 799-812, 2003.
(Summary)
SCF ubiquitin ligases, composed of three major subunits, Skp1, Cul1, and one of many F box proteins (Fbps), control the proteolysis of important cellular regulators. We have inactivated the gene encoding the Fbp beta-Trcp1 in mice. beta-Trcp1(-/-) males show reduced fertility correlating with an accumulation of methaphase I spermatocytes. beta-Trcp1(-/-) MEFs display a lengthened mitosis, centrosome overduplication, multipolar metaphase spindles, and misaligned chromosomes. Furthermore, cyclin A, cyclin B, and Emi1, an inhibitor of the anaphase promoting complex, are stabilized in mitotic beta-Trcp1(-/-) MEFs. Indeed, we demonstrate that Emi1 is a bona fide substrate of beta-Trcp1. In contrast, stabilization of beta-catenin and IkappaBalpha, two previously reported beta-Trcp1 substrates, does not occur in the absence of beta-Trcp1 and instead requires the additional silencing of beta-Trcp2 by siRNA. Thus, beta-Trcp1 regulates the timely order of meiotic and mitotic events.
S Sato, M Miyauchi, I Ogawa, Yasusei Kudo, S Kitagawa, M Hiraoka and Takashi Takata : Inhibition of CD44v9 upregulates the invasion ability of oral squamous cell carcinoma cells., Oral Oncology, Vol.39, No.1, 27-30, 2003.
(Summary)
The aim of the present study has been to determine the role of CD44v9 in the metastatic process of oral squamous cell carcinoma (OSCC). We have examined the expression intensity of CD44v9 in four OSCC cell lines, and using cell culture insert investigated the invasion ability of the cells expressing CD44v9 at higher levels (HSC-2, HSC-3), and the cells expressing this protein at lower levels (HSC-4, KB) with or without the treatment with an anti-CD44v9 antibody. In the highly expressing cells, the addition of anti-CD44v9 antibody enhanced their invasion ability, whereas it showed no effect on the invasion ability of the weakly expressing cells. These results suggest that the reduction of CD44v9 expression may weaken cell-to-cell adhesion in OSCC and make the tumor cells detach easily from their nests, resulting in the enhancement of their invasion ability. It may ultimately promote the establishment of a metastatic lesion.
A rare case is described of a solitary fibrous tumor (SFT) with malignant potential arising in the sublingual gland. A 59-year-old man presented with a 4-month history of a slowly enlarging painless mass in the center of the floor of the mouth. The tumor was a well-demarcated, firm mass with a multicystic lesion. The tumor exhibited highly cellular areas of spindle cells with patternless architecture alternating with hypocellular areas. The tumor cells were positive for CD34 and bcl-2 as well as vimentin, and negative for epithelial, myogenic, neurogenic and histiocytic markers. The tumor cells formed multiple satellite nodules around dilated ducts in the multicystic lesion, indicating infiltrative growth. In addition, areas exhibiting higher cellularity with increased mitoses were noticed in the satellite nodules, although cellular atypia was not obvious. These findings led to a final diagnosis of SFT with malignant potential. There has been no recurrence or metastasis for 27 months after the surgery. Solitary fibrous tumor of the salivary gland must be differentiated from various spindle cell neoplasms including myogenic, peripheral nerve sheath, fibroblastic and fibro-histiocytic spindle cell neoplasms, hemangiopericytoma and myoepithelioma. In addition to characteristic morphological features, an immunohistochemical positivity for CD34 and bcl-2 may aid in the diagnosis of SFT.
Naoki Matsuda, Miwa Horikawa, Masami Watanabe, Syoji Kitagawa, Yasusei Kudo and Takashi Takata : Possible involvement of extracellular signal-regulated kinases 1/2 in mitogenic response of periodontal ligament cells to enamel matrix derivative., European Journal of Oral Sciences, Vol.110, No.6, 439-444, 2002.
(Summary)
The efficacy of enamel matrix derivative (EMD) as an adjunct to periodontal regenerative therapy has been demonstrated in recent clinical studies, however, little is known about its molecular mechanism (s). We examined the mitogenic response of cultured periodontal ligament (PDL) cells to EMD and characterized associated changes in proliferation-related intracellular signaling molecules, including mitogen-activated protein kinases (MAPK) and Akt kinases/protein kinase B (Akt/PKB) kinases. The DNA synthesis of PDL cells increased following treatment with EMD at concentrations higher than 1 microg ml(-1). This mitogenic response to EMD was associated with the selective activation of extracellular signal-regulated kinase (ERK) 1/2. No other MAPKs, or Akt/PKB kinases, responded to EMD stimulation. The EMD induction of DNA synthesis and activation of ERK 1/2 were diminished by pretreatment with suramin, an inhibitor of receptor tyrosine kinases (RTK). The signaling pathway induced by EMD from RTK to ERK 1/2 was similar to that activated by epidermal growth factor (EGF), although the specific binding of 125I-EGF to PDL cells was not affected by pretreatment or concomitant treatment with EMD. These findings suggest that EMD elicits its mitogenic signal through an EMD-specific RTK towards ERK 1/2.
(Keyword)
Blotting, Western / Cell Division / Cells, Cultured / DNA Replication / Dental Enamel Proteins / Enzyme Activation / Epidermal Growth Factor / Fibroblasts / Humans / MAP Kinase Signaling System / Mitogen-Activated Protein Kinase 3 / Mitogen-Activated Protein Kinases / Mitogens / Periodontal Ligament / Phosphorylation / Protein Binding / Receptor Protein-Tyrosine Kinases
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12507217
Yasusei Kudo, M Hiraoka, S Kitagawa, Mutsumi Miyauchi, S Kakuo, M Zhao, T Ide and Takashi Takata : Establishment of human cementifying fibroma cell lines by transfection with temperature-sensitive simian virus-40 T-antigen gene and hTERT gene., Bone, Vol.30, No.5, 712-717, 2002.
(Summary)
Human cementifying fibroma (HCF) is a benign fibro-osseous neoplasm of periodontal ligament (PDL) origin containing varying amounts of mineralized material resembling cementum. In the present study, we established cell lines from HCF, which were detected in the mandible of a 54-year-old Japanese man. To obtain immortalized cell clones, we undertook transfection with temperature-sensitive simian virus-40 (SV40) T-antigen and hTERT into HCF cells. Cells transfected with SV40 T-antigen entered "crisis" state between passages 22 and 35, but activation of telomerase by transfection with hTERT in the SV40-transformed HCF cells resulted in bypass of the crisis and maintenance over passage 200. HCF cell lines decreased the expression of SV40 T-antigen and the activity of cell proliferation at a nonpermissive temperature (39 degrees C) in comparison with that at a permissive temperature (33 degrees C). High activities of alkaline phosphatase and mineralization and the expression of type I collagen, osteocalcin, osteopontin, and bone sialoprotein by reverse transcription-polymerase chain reaction (RT-PCR) were observed in HCF cells at 39 degrees C. Overall, these findings suggest that: (i) HCF cell lines may represent a novel in vitro human cell model for the study of the regulatory mechanism of differentiation and proliferation of the human PDL; and (ii) transfection of plasmids encoding the temperature-sensitive SV40 T-antigen gene and hTERT gene may be useful for obtaining immortalized cell lines from benign human tumor and, probably, nonneoplastic human tissues.
Rosy Leonardi, Giuseppe Pannone, Gaetano Magro, Yasusei Kudo, Takashi Takata and Lorenzo Muzio Lo : Differential expression of heat shock protein 27 in normal oral mucosa, oral epithelial dysplasia and squamous cell carcinoma., Oncology Reports, Vol.9, No.2, 261-266, 2002.
(Summary)
The aim of this study was to evaluate HSP27 expression in fetal, normal and inflamed oral mucosal epithelium and in oral premalignant epithelial lesions and in their ensuing invasive cancers. In developing human oral epithelia, immunoreactions for HSP27 were moderately observed in suprabasal keratinocytes of palate and tongue. Normal oral epithelium had an intense suprabasal positivity. In inflamed oral mucosa, HSP27 staining was stronger in basal and suprabasal keratinocytes than in normal epithelium. Most oral premalignant lesions showed no (5 cases, 29%) or low (8 cases, 46.4%) staining. In OSCC both low and high HSP27 levels of expression were observed. HSP27 immunolabelling was down-regulated in poorly differentiated areas and up-regulated in highly differentiated ones. These findings indicated that HSP27 expression seems to protect cells from apoptosis during inflammation, while the down-regulation in dysplasia could impair the protective mechanism against mutagenesis induced by environmental factors and thus enhancing the transformation of oral epithelial dysplasia into OSCCs.
Yasusei Kudo, S Kitajima, S Sato, M Miyauchi, I Ogawa and Takashi Takata : High expression of S-phase kinase-interacting protein 2, human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas., Cancer Research, Vol.61, No.19, 7044-7047, 2001.
(Summary)
Reduced expression of p27(Kip1), a cyclin-dependent kinase (Cdk) inhibitor, is frequently found in various cancers, including oral squamous cell carcinoma (OSCC), and is attributable to an enhancement of its degradation. Skp2, an F-box protein necessary for DNA replication, is required for the ubiquitinylation and subsequent degradation of p27(Kip1). In the present study, we examined the expression of Skp2 and its correlation with the expression of p27(Kip1) protein or p27(Kip1) degradation in OSCC. Using immunohistochemistry, we found that high expression of Skp2 was present in 49% of OSCCs and only 20% of epithelial dysplasias. Significantly, high expression of Skp2 was correlated with poor prognosis of OSCC patients. We also found an inverse correlation between the expression of Skp2 and p27 by immunohistochemical analysis. A similar correlation was observed in OSCC cell lines and OSCC tissues by Western blot analysis. Interestingly, OSCC tissues with Skp2 expression had high p27(Kip1) degradation activity. These findings indicate that (a) Skp2 may play an important role for the development of OSCC, (b) Skp2 can be a novel target for OSCC treatment as well as a strong prognostic marker, and (c) the reduction in p27(Kip1) protein may be brought about by enhancement of its degradation mediated by increased levels of Skp2 protein.
Mutsumi Miyauchi, S Sato, S Kitagawa, M Hiraoka, Yasusei Kudo, I Ogawa, M Zhao and Takashi Takata : Cytokine expression in rat molar gingival periodontal tissues after topical application of lipopolysaccharide., Histochemistry and Cell Biology, Vol.116, No.1, 57-62, 2001.
(Summary)
It is well known that proinflammatory cytokines produced by host cells play an important role in periodontal tissue destruction. However, the localization of the cytokines in in vivo periodontal tissues during development of periodontal disease has not been determined. Immunohistochemical expression of proinflammatory cytokines including IL-1alpha, IL-1beta, and TNF-alpha was examined at 1 and 3 h, and 1, 2, 3, and 7 days after topical application of lipopolysaccharide (LPS; 5 mg/ml in physiological saline) from E. coli into the rat molar gingival sulcus. In the normal periodontal tissues, a small number of cytokine-positive epithelial cells were seen in the junctional epithelium (JE), oral sulcular and oral gingival epithelium, in addition to macrophages infiltrating in the subjunctional epithelial area and osteoblasts lining the alveolar bone surface. Epithelial remnants of Malassez existing throughout periodontal ligament were intensely positive for IL-1beta but negative for the other two cytokines. At 3 h after the LPS treatment, almost all cells in the JE were strongly positive for the cytokines examined. In addition, several cytokine-positive cells, including neutrophils, macrophages, and fibroblasts, were seen in the subjunctional epithelial connective tissue. At day 2, expression of the cytokines in the JE gradually decreased, while cytokine-positive cells in the connective tissue increased in number. Positive staining of the cytokines was seen in osteoclasts and preosteoclasts which appeared along the alveolar bone margin in this period. The number of cytokine-positive cells decreased by day 7. These findings indicate that, in addition to macrophages, neutrophils, and fibroblasts, the JE cells are a potent source of TNF-alpha, IL-1alpha, and IL-1beta reacting to LPS application, and suggest that JE cells may play an important role in the first line of defense against LPS challenge, and the proinflammatory cytokines transiently produced by various host cells may be involved in the initiation of inflammation and subsequent periodontal tissue destruction.
P H Philipsen, A P Reichart, H Nikai, Takashi Takata and Yasusei Kudo : Peripheral ameloblastoma: biological profile based on 160 cases from the literature., Oral Oncology, Vol.37, No.1, 17-27, 2001.
(Summary)
The present profile of the peripheral ameloblastoma (PA) is based on a literature survey of 160 published tumour cases. The PA is an exophytic growth localized to the soft tissues overlying the tooth-bearing areas of the jaws, the initial diagnosis often being fibrous epulis. In most cases there is no radiological evidence of bone involvement, but a superficial bone erosion--known as cupping or saucerization--may be detected at operation. The PA accounts for 2-10% of all ameloblastomas. The overall average age is 52.1 years, slightly higher for males (52.9 years) than for females (50.6 years). Thus, the PA occurs at a significantly higher age than the intraosseous ameloblastoma (IA; 37.4 years). The male/female ratio amounts to 1.9:1, as opposed to 1.2:1 for the IA. The male/female ratio for the Japanese cases included in this survey is 2.5:1 as opposed to that of non-Japanese cases 1.4:1. As to the location of PA, the maxilla/mandible ratio is 1:2.6. The mandibular premolar region accounts for 32.6% of all sites. Five extra-gingival lesions have been reported under the term PA. As these cases most likely represent salivary gland tumours, they are not accepted under the diagnosis of PA. The odontogenic gingival epithelial hamartoma shows clinical, histological and behavioural features almost identical to the PA, and it is discussed whether this lesion and the PA should be considered one and the same entity. Pathogenetically, two major sources are discussed: remnants of the dental lamina and the oral surface epithelium. Histologically, the PA consists of proliferating odontogenic epithelium exhibiting the same histomorphological cell types and patterns as seen in the IA. The stroma is that of a mature, fibrous connective tissue. The indolent biological behaviour dictates a conservative therapeutical approach. It is discussed whether PA is a true neoplastic counterpart of the IA or rather an odontogenic hamartomatous lesion. Six cases of malignant PA have been reported.
(Keyword)
Adult / Age Distribution / Aged / Ameloblastoma / Diagnosis, Differential / Female / Humans / Jaw Neoplasms / Male / Middle Aged / Neoplasm Recurrence, Local / Sex Distribution / Soft Tissue Neoplasms
S Sato, Mutsumi Miyauchi, T Takekoshi, M Zhao, Yasusei Kudo, I Ogawa, S Kitagawa, M Fujita and Takashi Takata : Reduced expression of CD44 variant 9 is related to lymph node metastasis and poor survival in squamous cell carcinoma of tongue., Oral Oncology, Vol.36, No.6, 545-549, 2000.
(Summary)
Expression of CD44v9 was immunohistochemically studied in 120 biopsy specimens from primary squamous cell carcinoma (SCC) of the tongue and correlated with clinicopathological findings of the SCCs. The tumors were classified into three groups according to immunostaining pattern of CD44v9; 53 cases with distinct positivity in all cancer cells except for those in the central part of nests (Group 1, non-reduced group), 42 cases with reduced expression in peripheral cells of nests (Group 2, reduced group), and 25 cases with complete disappearance of the expression in one or more nests (Group 3, negative group). Nineteen of 25 (76%) tumors in Group 3 and 14 of 42 (33%) in Group 2 exhibited lymph node metastasis, compared with only 8 of 53 (15%) in Group 1. The average survival time in Groups 1, 2 and 3 was 4496+/-204, 3866+/-379 and 2719+/-359 days, respectively and became shorter with the reduction of CD44v9 expression. These results suggest that the down-regulation of CD44v9 in SCC of the tongue may relate to the detachment of tumor cells from primary lesions, establishment of lymph node metastasis and consequently the death of patients.
Yasusei Kudo, Takashi Takata, I Ogawa, M Zhao, S Sato, T Takekoshi, Mutsumi Miyauchi and H Nikai : Reduced expression of p27(Kip1) correlates with an early stage of cancer invasion in oral squamous cell carcinoma., Cancer Letters, Vol.151, No.2, 217-222, 2000.
(Summary)
Down-regulation of p27(Kip1) has been reported to correlate with poor survival of various carcinoma patients including oral squamous cell carcinomas (OSCCs). It is still unclear, however, at what stage of oral carcinogenesis the down-regulation of this protein occurs. In this study, therefore, we evaluated immunoexpression of p27(Kip1) protein in 17 cases of oral epithelial dysplasia and succeeding invasive OSCC in the same patient. We reported here that 88% cases showed high p27(Kip1) expression in dysplastic lesions, whereas 82% cases of succeeding invasive OSCC exhibited reduced expression. The reduction of p27(Kip1) expression was also observed in 16 of 19 (84%) early invasive lesions and well correlated with Ki-67 expression which is good indicator of cell proliferation. We also investigated immunoexpression of p53 protein of which abnormality has been known to occur during the early stage of OSCC development. Overexpression of p53 protein was demonstrated in 29% of dysplastic lesions, 42% of early invasive and 71% of invasive OSCCs. These findings suggest that abnormalities of both p53 and p27(Kip1) are involved in the carcinogenesis of OSCC, but they seem to play their role at different stages of oral cancer development, respectively. Reduced expression of p27(Kip1) may concern the cancer invasion directly or indirectly as well as abnormal proliferation.
Takashi Takata, Mutsumi Miyauchi, I Ogawa, Yasusei Kudo, T Takekoshi, M Zhao, S Sato, H Nikai and K Komiyama : Immunoexpression of transforming growth factor beta in desmoplastic ameloblastoma., Virchows Archiv, Vol.436, No.4, 319-323, 2000.
(Summary)
Desmoplastic ameloblastoma (DA) is an unusual subtype of ameloblastoma histologically characterized by the pronounced collagenized stroma. In the present study, the immunolocalization of transforming growth factor beta (TGF-beta), one of the most potent local factors for modulating extracellular matrix formation, was observed in DA in order to study its participation in the stromal desmoplasia. Seven cases of DA, including a "hybrid" lesion, were studied together with ten cases of ordinary follicular and plexiform ameloblastomas as the control. In contrast to ordinary ameloblastomas, marked immunoexpression was observed in all DAs but one. In the "hybrid" lesion, TGF-beta was not expressed in the area of follicular ameloblastoma but in that of DA. These results show that TGF-beta produced by tumor cells of DA plays a part in the desmoplastic matrix formation.
Takashi Takata, M Zhao, T Uchida, Yasusei Kudo, S Sato and H Nikai : Immunohistochemical demonstration of an enamel sheath protein, sheathlin, in odontogenic tumors., Virchows Archiv, Vol.436, No.4, 324-329, 2000.
(Summary)
Enamel proteins can be useful markers for assessment of the functional differentiation of neoplastic epithelium and the nature of extracellular matrices in odontogenic tumors. In the present study, we examined immunohistochemical localization of sheathlin, a recently cloned enamel sheath protein, in various odontogenic tumors to evaluate functional differentiation of tumor cells and the nature of hyalinous or calcified matrices in odontogenic neoplasms. Distinct immunolocalization of sheathlin was observed in the immature enamel of the tooth germ at the late bell stage. Secretory ameloblasts facing the enamel matrix also showed positive staining in their cytoplasm. Definite localization of sheathlin was demonstrated in the enamel matrix in odontogenic tumors with inductive dental hard tissue formation such as ameloblastic fibroodontomas and odontomas. Immunoexpression of sheathlin was, furthermore, demonstrated in eosinophilic droplets in solid nests of adenomatoid odontogenic tumor (AOT) and ghost cells in the epithelial lining of calcifying odontogenic cyst (COC). In AOT, cells facing the eosinophilic droplets also expressed the protein in their cytoplasm. There was neither intracellular staining for sheathlin in the tumor cells nor extracellular staining in the matrix of ameloblastomas and calcifying epithelial odontogenic tumors. Dentin, dysplastic dentin-like hyaline material and cementum in the tumors examined were negative for sheathlin. These results show that immunodetection of sheathlin is a useful marker for functional differentiation of secretory ameloblasts and enamel matrix, which is often hard to differentiate from other hard tissues in odontogenic tumors. Our findings from the view point of sheathlin expression support that the tumor cells of ameloblastomas do not attain full differentiation into functional ameloblasts. It is very interesting that epithelial cells in odontogenic tumors can differentiate into functional ameloblasts without induction by odontogenic mesenchyme, as shown by immunoexpression of sheathlin in eosinophilic droplets within solid epithelial sheets in AOT and ghost cells in the epithelial lining of COC where inductive participation of mesenchymal cells was most unlikely.
Yasusei Kudo, Takashi Takata, I Ogawa, T Kaneda, S Sato, T Takekoshi, M Zhao, M Miyauchi and H Nikai : p27Kip1 accumulation by inhibition of proteasome function induces apoptosis in oral squamous cell carcinoma cells., Clinical Cancer Research, Vol.6, No.3, 916-923, 2000.
(Summary)
Ubiquitin-mediated proteolysis controls intracellular levels of various cell cycle regulatory proteins, and its inhibition has been shown to induce apoptosis in proliferating cells. In the present study, we examined induction of apoptosis in oral squamous cell carcinoma (OSCC) cells by treatment with specific proteasome inhibitors, carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal and lactacystin. In all three OSCC cell lines examined, apoptotic changes such as apoptotic body formation and DNA fragmentation were observed at various degrees after 24 h of the carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal or lactacystin treatment. HSC2 cells showed the most prominent apoptotic changes among the cell lines examined and demonstrated the highest level of accumulation of p27Kip1 protein after the treatment with proteasome inhibitor. Reduced expressions of cyclin D1 and phospho pRb were also observed after the treatment with proteasome inhibitor. Moreover, 12 h of treatment with the proteasome inhibitor inhibited cdk2/cyclin E kinase activity and increased the ratio of the cell cycle population at the G1 phase. The proteasome inhibitor led to inhibition of cell cycle progression. In addition, activation of CPP32 and reduced expression of Bcl-2 were observed. Because apoptosis induced by the proteasome inhibitor was inhibited by treatment with antisense p27Kip1 oligonucleotide, accumulation of the p27Kip1 protein might play an important role in the apoptosis induced by proteasome inhibitor. The present results suggest that inhibition of proteasome function may be used as a possible target of novel therapy for OSCC.
J Fujimoto, W Yasui, H Tahara, E Tahara, Yasusei Kudo, H Yokozaki and E Tahara : DNA hypermethylation at the pS2 promoter region is associated with early stage of stomach carcinogenesis., Cancer Letters, Vol.149, No.1-2, 125-134, 2000.
(Summary)
pS2, a member of the trefoil peptide family, has been suggested to be a gastric-specific tumor suppressor. We examined the expression of pS2 in gastric carcinomas, adenomas and non-neoplastic mucosa and analyzed the DNA methylation in the pS2 promoter. Reduced expression of pS2 was frequently associated with well-differentiated adenocarcinomas. The CpG sites within the promoter region of the pS2 gene were methylated in pS2-negative gastric carcinoma cell lines whereas it was not in pS2-positive cell line. The promoter methylation was detected in gastric carcinoma tissues and intestinal metaplasia with reduced pS2 expression whereas none of the carcinomas with preserved pS2 expression showed the promoter methylation. These findings suggest that reduced expression of pS2 due to the promoter methylation may participate in an early stage of stomach carcinogenesis, especially of well differentiated type.
M Zhao, Takashi Takata, Yasusei Kudo, S Sato, I Ogawa, K Wakida, T Uchida and H Nikai : Biosynthesis of glycosaminoglycans and aggrecan by tumor cells in salivary pleomorphic adenoma: ultrastructural evidence., Journal of Oral Pathology & Medicine, Vol.28, No.10, 442-450, 1999.
(Summary)
The present study attempted to discover the sites of synthesis of various glycosaminoglycans (GAGs) and aggrecan in salivary pleomorphic adenoma (PA) with the use of a highly sensitive and specific post-embedding immunogold-silver staining technique at the ultrastructural level. Silver particles representing various GAGs and aggrecan were found to accumulate frequently in the intercellular spaces of non-luminal cells in the epithelial clusters and were dispersed in the myxoid matrix of the mesenchyme-like areas. Furthermore, the non-luminal epithelial cells were demonstrated to contain immunopositive intracytoplasmic vesicles and vacuoles, some of which were of Golgi complex origin. In contrast, intracellular silver particles for hyaluronic acid were mostly attached to the inner surface of the cell membrane. These observations agree well with the current theories of the biosynthesis of GAGs and proteoglycans and provide direct evidence for the production of various GAGs and aggrecan by tumor epithelial cells of PA. Such findings support the ideas that in PA a loss of epithelium occurs by stromalization following epithelial secretion of extracellular matrix substances and transformation of epithelium to mesenchyme represents the basic principle of the tissue heterogeneity in this tumor.
Takashi Takata, Mutsumi Miyauchi, I Ogawa, M Zhao, Yasusei Kudo, S Sato, T Takekoshi, H Nikai and K Tanimoto : So-called 'hybrid' lesion of desmoplastic and conventional ameloblastoma: report of a case and review of the literature., Pathology International, Vol.49, No.11, 1014-1018, 1999.
(Summary)
So-called 'hybrid' lesion of ameloblastoma, which is composed of desmoplastic ameloblastoma and conventional follicular/plexiform ameloblastoma, is an unusual variant of ameloblastoma and only eight cases of 'hybrid' lesion have been published in the English literature. To enhance knowledge of this interesting tumor, we add a case of 'hybrid' lesion that occurred in the right mandible of a 48-year-old Japanese male. Radiographic examination disclosed a honeycomb appearance at the anterior alveolar region, combined with a unicystic radiolucency in the molar region of the mandibular body. Histologically, the former showed microscopic features of desmoplastic ameloblastoma and the latter those of follicular ameloblastoma with focal granular cell transformation. The lesion was enucleated with curettage of surrounding bone and the lesional cavity was marsupialized. Although tumor tissues reappeared at 3, 5, 7 and 14 months after the surgery, the patient has remained disease free for 11 years after the last vaporization by CO2 laser of the recurred tumor. Many more cases of 'hybrid' lesion are needed to clarify the clinicopathological, histopathological and biological characteristics of this interesting variant of ameloblastoma.
(Keyword)
Ameloblastoma / Humans / Laser Therapy / Male / Mandibular Neoplasms / Middle Aged / Neoplasm Recurrence, Local
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10594850
Takashi Takata, Yasusei Kudo, M Zhao, I Ogawa, Mutsumi Miyauchi, S Sato, J Cheng and H Nikai : Reduced expression of p27(Kip1) protein in relation to salivary adenoid cystic carcinoma metastasis., Cancer, Vol.86, No.6, 928-935, 1999.
(Summary)
Overall, these findings suggest that reduced expression of p27(Kip1) may correlate with the development and progression of salivary ACC and can be an indicator of its malignant behavior. They also suggest that increased proteasome-mediated degradation may play an important role in this reduction of p27(Kip1) expression.
Yasusei Kudo, Takashi Takata, I Ogawa, S Sato and H Nikai : Expression of p53 and p21CIP1/WAF1 proteins in oral epithelial dysplasias and squamous cell carcinomas., Oncology Reports, Vol.6, No.3, 539-545, 1999.
(Summary)
The expression of tumor suppressor gene, p53 and cyclin-dependent kinase inhibitor, p21 in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC) was examined immunohistochemically and its relationship with clinicopathological findings was analyzed. Among 24 epithelial dysplasias, 4 cases (17%) expressed p53 protein and 23 cases (96%) expressed p21 protein. On the other hand, expression of p53 was observed in 64% of OSCCs, and expression of p21 was observed in 77% of OSCCs. In the analyses of the correlation between the expression of p53 and p21 in epithelial dysplasia and OSCC, 79% of epithelial dysplasias were p53-negative and p21-positive, compared to 25% of the OSCCs. p21 expression did not correlate with p53 expression. These results were also demonstrated in OSCC cell lines by western blot analysis. Cumulative survival rate of the patients p53-negative and p21-positive was higher than those p53-positive and p21-negative, those p53-negative and p21-negative and those p53-positive and p21-positive. These findings suggest that p53 expression and p21 negative expression may involve in neoplastic transformation of oral epithelium. In the present study, we did not observe correlation between the expression of p53 and p21 proteins in OSCC. p21 expression may be regulated by p53-independent pathways as well as p53-dependent ones. However, combination of the p21 and p53 expression may be useful as a prognostic marker.
Takashi Takata, Mutsumi Miyauchi, H Ito, I Ogawa, Yasusei Kudo, M Zhao, S Sato, T Takekoshi, H Nikai and K Tanimoto : Clinical and histopathological analyses of desmoplastic ameloblastoma., Pathology, Research and Practice, Vol.195, No.10, 669-675, 1999.
(Summary)
Desmoplastic ameloblastoma (DA) is an unusual subtype of ameloblastoma characterized by pronounced desmoplastic stroma. There is, however, still argument whether DA is a distinct clinicopathologic entity. To enhance knowledge of DA, 7 cases of DA (7.9%) were retrieved from 89 ameloblastomas field in the Department of Oral Pathology, Hiroshima University School of Dentistry and analyzed clinicopathologically and histopathologically. The mean age of the patients with DA and non-DA at the time of the diagnosis was 40.6 +/- 5.9 years and 33.1 +/- 2.0 years, respectively. The male-to-female ratio was 2.5:1 in DA and 1.8:1 in non-DA. Four (57%) DAs were located in the maxilla where only 6% of the non-DA occurred. Interestingly, all DAs arose in the anterior/premolar area of the jaws and 6 cases were located mainly within the alveolus. None of the DA showed typical radiographic features of ameloblastoma. In 5 DAs, scattered radiopacities were observed in the radiolucent lesion and gave preoperative diagnoses of non-ameloblastomatous lesions or even osteosarcoma. All DAs showed pronounced desmoplastic stroma where there were compressed tumor islands usually lacking a peripheral layer of ameloblastic cells and a central zone of stellate reticulum. There was cystic change within the epithelial nests in 3 DAs and true glandular structures with mucus cells in a case of DA. Tumor islands often infiltrated into marrow spaces of surrounding bone. There was no capsule formation. Recurrence rate was 14% in DA and 20% in non-DA. The present study based on data of DA in the Japanese population supports that DA must be considered as a distinct clinicopathologic entity.
(Keyword)
Adolescent / Adult / Age Distribution / Aged / Ameloblastoma / Child / Child, Preschool / Female / Humans / Male / Mandibular Neoplasms / Maxillary Neoplasms / Middle Aged / Recurrence / Sex Distribution / Stromal Cells
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10549030
Yasusei Kudo, Takashi Takata, W Yasui, I Ogawa, Mutsumi Miyauchi, T Takekoshi, E Tahara and H Nikai : Reduced expression of cyclin-dependent kinase inhibitor p27Kip1 is an indicator of malignant behavior in oral squamous cell carcinoma., Cancer, Vol.83, No.12, 2447-2455, 1998.
(Summary)
These findings suggest that 1) reduced expression of p27Kip1 may correlate with the development and progression of OSCC and can be an indicator of malignant behavior of this neoplasm, and 2) increased proteasome-mediated degradation may play an important role in the reduction of p27Kip1 protein expression.
Mutsumi Miyauchi, Takashi Takata, H Ito, I Ogawa, Yasusei Kudo, T Takekoshi and H Nikai : Distribution of macrophage lineage cells in rat gingival tissue after topical application of lipopolysaccharide: an immunohistochemical study using monoclonal antibodies: OX6, ED1 and ED2., Journal of Periodontal Research, Vol.33, No.6, 345-351, 1998.
(Summary)
To discuss the role of macrophage lineage cells on the periodontal tissue destruction, we immunohistochemically examined the phenotype and the dynamics of macrophage lineage cells 1 or 3 h or 1, 2, 3 or 7 d after topical application of LPS (5 mg/ml in physiological saline) from the rat gingival sulcus using 3 monoclonal antibodies: OX6 (antigen-presenting cells), ED1 (monocytes, macrophages and dendritic cells) and ED2 (resident macrophages). We could detect at least 3 different types of macrophage lineage cells, namely OX6+/ED1+/ED2- dendritic cells and exudate macrophages and ED2+ resident macrophages. After LPS application the majority of macrophage lineage cells accumulated in the subjunctional epithelial area were newly extravasated OX6+/ED1+/ED2- dendritic cells or macrophages. The number of these cells increased progressively with time and reached a maximum level at d 2. On the other hand, number and tissue distribution of ED2+ resident macrophages did not change. These results indicate that several types of macrophage lineage cells exist in rat gingival tissue and suggest that dendritic cells and exudate macrophages transiently accumulated after LPS application are responsible for various host immune response and tissue destruction caused by LPS.
W Yasui, Yasusei Kudo, K Naka, J Fujimoto, T Ue, H Yokozaki and E Tahara : Expression of CD44 containing variant exon 9 (CD44v9) in gastric adenomas and adenocarcinomas: relation to the proliferation and progression., International Journal of Oncology, Vol.12, No.6, 1253-1258, 1998.
(Summary)
The expression of CD44 splice variant containing exon 14 (variant exon 9: CD44v9) was examined immunohistochemically in non-neoplastic mucosa, adenoma and adenocarcinoma of the stomach and analyzed the relation with the expression of Ki-67 antigen and p53 protein. In non-neoplastic gastric mucosa, basolateral membrane of the epithelial cells in the pyloric glands showed the expression of CD44v9. The epithelial cells in the intestinal metaplastic mucosa of the stomach sometimes expressed CD44v9. In the neoplastic lesions, the expression of CD44v9 was detected in 20% (34/170) of the adenomas and 28% (132/478) of the adenocarcinomas, respectively. The incidence of CD44v9 expression did not differ among histological type of gastric carcinoma. Twelve per cent of the adenocarcinomas showed strong expression of CD44v9, whereas non of the adenomas did. The incidence of CD44v9 expression was significantly higher in carcinomas invading into muscularis propria or the cases of stages 3 and 4 in comparison with that in carcinomas limited to submucosa or the stages 1 and 2 cases (p<0.05). The incidence of positive cases was higher in carcinomas with lymph node metastasis than those without metastasis (p<0.05). The expression of CD44v9 was significantly correlated with the expression of Ki-67 (p<0.05). It was also correlated with the expression of p53 protein in the tumor cells (p<0.01). These findings overall suggest that the expression of CD44v9 may be associated with the development as well as progression of the gastric carcinomas.
Yasusei Kudo, W Yasui, T Ue, S Yamamoto, H Yokozaki, H Nikai and E Tahara : Overexpression of cyclin-dependent kinase-activating CDC25B phosphatase in human gastric carcinomas., Gann : Japanese Journal of Cancer Research, Vol.88, No.10, 947-952, 1997.
(Summary)
CDC25 phosphatases activate cyclin-dependent kinases by removing inhibitory phosphate groups on the molecules and positively regulate the cell cycle progression. The expression of CDC25A, B and C was examined in gastric carcinoma cell lines and gastric carcinoma tissues by northern blotting and immunohistochemistry. The gastric carcinoma cell lines expressed CDC25A, B and C mRNA at various levels. The expression levels of CDC25B were generally higher than those of CDC25A and C. Of the 40 gastric carcinomas, 70% of the tumors expressed CDC25B mRNA at higher levels than the corresponding normal mucosas, while 38% overexpressed CDC25A mRNA. The CDC25C expression was at very low or undetectable levels. No obvious correlation was detected between the expression of CDC25B and p53 gene mutations. Immunohistochemically, CDC25-positive tumor cells were detected in 43 (78%) of 55 gastric carcinoma cases, of which 27 (49%) were strongly positive. Strong expression of CDC25B protein was associated with advanced stage and deep invasion. Furthermore, the incidence of strong expression was significantly higher in carcinomas with nodal metastasis than in those without metastasis. These findings suggest that overexpression of CDC25B may favor development and progression and may be an indicator of malignant behavior of gastric carcinomas.
W Yasui, Y Akama, H Yokozaki, S Semba, Yasusei Kudo, F Shimamoto and E Tahara : Expression of p21(WAF1/CIP1) in colorectal adenomas and adenocarcinomas and its correlation with p53 protein expression., Pathology International, Vol.47, No.7, 470-477, 1997.
(Summary)
The expression of p53-inducible cyclin-dependent kinase inhibitor, p21WAF1/CIP1 in non-neoplastic mucosa, adenoma and adenocarcinoma of the colorectum was examined by immunohistochemistry and western blotting and its relation with the expression of p53 protein was analyzed. Non-neoplastic epithelial cells at the surface area showing no proliferative activity expressed p21WAF1/CIP1. The expression of p21WAF1/CIP1 was immunohistochemically detected in 55% (206/377) of the adenomas and 66% (190/289) of the adenocarcinomas, respectively. The incidence of strongly positive cases was significantly higher in the adenocarcinomas (27%) than in the adenomas (18%) (P < 0.05). The incidence of cases with strong p21WAF1/CIP1 expression was higher in stages 0, 1 and 2 carcinomas than in stages 3 and 4 carcinomas (P < 0.05). A decrease in the incidence of cases with strong expression was detected in carcinomas invading deeper than muscularis propria. The incidence of strongly positive cases was significantly lower in carcinomas with lymph node metastasis than those without metastasis (P < 0.05). The expression of p21 as well as p53 detected by western blotting was compatible with the results of immunohistochemistry in most cases examined. However, there was no significant correlation between the expression of p21WAF1/CIP1 and the abnormal accumulation of p53. These findings overall suggest that: (i) the physiological expression of p21WAF1/CIP1 may be associated with cellular senescence of colorectal mucosa; (ii) reduced expression of p21WAF1/CIP1 may participate in the progression of colorectal carcinoma; and (iii) p53-independent pathway may be considerably involved in the induction of p21WAF1/CIP1.
W Yasui, Yasusei Kudo, S Semba, H Yokozaki and E Tahara : Reduced expression of cyclin-dependent kinase inhibitor p27Kip1 is associated with advanced stage and invasiveness of gastric carcinomas., Gann : Japanese Journal of Cancer Research, Vol.88, No.7, 625-629, 1997.
(Summary)
Reduced expression of a cyclin-dependent kinase inhibitor p27Kip1 has recently been shown to predict poor survival of patients with breast and colorectal cancers. We studied the expression of p27Kip1 in gastric carcinomas by northern blotting, western blotting and immunohistochemistry to determine whether lack of p27 has implications for aggressiveness of gastric cancer. Reduced expression of p27 was detected in 40% of the gastric carcinomas at the mRNA level, while it was detected in 57% at the protein level. No gross alterations of the p27 gene were observed in any of the cases examined by Southern blot analysis. Immunohistochemical studies revealed that the expression of p27 was well preserved in most of the gastric adenomas, whereas it was so in only 26% of the gastric carcinomas. Fifty-six percent of the carcinomas showed almost no p27-positive cells. Decrease of p27-positive cells significantly correlated with advanced stage, depth of tumor invasion and lymph node metastasis. The expression of p27 showed an inverse correlation with the expression of cyclin E. These findings suggest that reduction of p27Kip1 protein may reflect the progression of gastric carcinomas and may be an indicator of high-grade malignancy.
I Ogawa, Takashi Takata, Mutsumi Miyauchi, H Ito, M Zhao, Yasusei Kudo and H Nikai : nm23-H1 expression in salivary adenoid cystic carcinoma in relation to metastasis and survival., Oncology Reports, Vol.4, No.4, 707-711, 1997.
(Summary)
The expression of nm23-H1, product of putative metastasis suppressor gene, was evaluated immunohistochemically in 31 cases of adenoid cystic carcinoma (ACC) of salivary glands and correlated with their clinicopathologic features. All benign salivary gland tumors of various types, which were used as a non-metastatic control, showed obvious nm23-H1 expression. The immunoreactivity of tumor cells was stronger than that of normal salivary gland components, although the distribution patterns of positive cells considerably varied between tumor types. In ACC, 16 cases (52%) showed the reduction of nm23-H1 immunoreactivity either in positive cell frequency or staining intensity. These cases were referred to as negative cases. The incidence of negative cases was 67% (10/15) and 38% (6/16) of the cases with and without metastasis, respectively. Furthermore, metastatic tumors showed decreased immunoreactivity of this protein compared with their primary tumors. The prognosis of patients with a nm23 negative tumor was generally poorer than that with a positive tumor. These results may suggest that the reduction of nm23-H1 protein has an implication for metastasis of ACC.
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21590125
Hidesuke Tada, Wenhua Shao, Naozumi Ishimaru and Yasusei Kudo : The life in Japan and status of private dental office at the times of COVID-19., Oral Diseases, Vol.27 Suppl 3, 727-729, 2020.
(Keyword)
COVID-19 / Dental Offices / Humans / Japan / SARS-CoV-2
Yasusei Kudo : Tumorigenesis and Development of Oral Cancer : Molecular Mechanism on Proliferation and Invasion, Journal of Oral Health and Biosciences, Vol.34, No.2, 26-33, Mar. 2022.
M Samadarani B S Siriwardena, Takaaki Tsunematsu, Guangying Qi, Naozumi Ishimaru and Yasusei Kudo : Invasion-Related Factors as Potential Diagnostic and Therapeutic Targets in Oral Squamous Cell Carcinoma-A Review., International Journal of Molecular Sciences, Vol.19, No.5, May 2018.
(Summary)
It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)-the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC.
Guangying Qi, Jing Liu, Sisi Mi, Takaaki Tsunematsu, Shengjian Jin, Wenhua Shao, Tian Liu, Naozumi Ishimaru, Bo Tang and Yasusei Kudo : Aurora Kinase Inhibitors In Head And Neck Cancer., Current Topics in Medicinal Chemistry, Vol.18, No.3, 199-213, Jan. 2018.
(Summary)
Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represents a new direction in cancer treatment. This paper reviews studies on Aurora kinases from recent years, including studies of their biological function, their relationship with tumor progression, and their inhibitors.
Masako Saito, Kunihiro Otsuka, Aya Ushio, Akiko Yamada, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : Unique Phenotypes and Functions of Follicular Helper T Cell and Regulatory T Cell in Sjögren's Syndrome., Current Rheumatology Reviews, Vol.14, No.3, 239-245, Jan. 2017.
(Summary)
Sjögren's syndrome (SS) is a T cell-mediated autoimmune disease of the systemic exocrine glands, such as salivary and lacrimal glands. A variety of T-cell subpopulations maintain immune tolerance in the thymus and periphery through complex immune responses including cellular and humoral immunity. The T-cell subpopulations exhibiting abnormal or unique phenotypes and impaired functionality have been reported to play important roles in the cellular mechanisms of autoimmunity in SS patients and animal models of SS. In this review, we focused on follicular helper T cells related to antibody production and regulatory T cells to control immune tolerance in the pathogenesis of SS. The unique roles of these T-cell subpopulations in the process of the onset or development of SS have been demonstrated in this review of recent publications. The clinical application of these T-cell subpopulations will be helpful for the development of new techniques for diagnosis or treatment of SS in the future.
Yasusei Kudo, Tada Hidesuke, Natsumi Fujiwara, Tada Yoshiko, Takaaki Tsunematsu, Yoichiro Miyake and Naozumi Ishimaru : Oral environment and cancer, Genes and Environment, Vol.38, No.13, Aug. 2016.
(Summary)
Cancer is now the leading cause of death in Japan. A rapid increase in cancer mortality is expected as Japan is facing a super-aged society. Many causes of cancer are known to be closely linked to life style factors, such as smoking, drinking, and diet. The oral environment is known to be involved in the pathogenesis and development of various diseases such as bronchitis, pneumonia, diabetes, heart disease, and dementia. Because the oral cavity acts as the bodily entrance for air and food, it is constantly exposed to foreign substances, including bacteria and viruses. A large number of bacteria are endemic to the oral cavity, and indigenous oral flora act to prevent the settlement of foreign bacteria. The oral environment is influenced by local factors, including dental plaque, tartar, teeth alignment, occlusion, an incompatible prosthesis, and bad lifestyle habits, and systemic factors, including smoking, consumption of alcohol, irregular lifestyle and eating habits, obesity, stress, hormones, and heredity. It has recently been revealed that the oral environment is associated with cancer. In particular, commensal bacteria in the oral cavity are involved in the development of cancer. Moreover, Candida, human papilloma virus and Epstein-Barr virus as well as commensal bacteria have been reported to be associated with the pathogenesis of cancer. In this review, we introduce recent findings of the correlation between the oral environment and cancer.
(Keyword)
cancer / Oral environment / bacteria / Candida / Human papilloma virus / Epstein-Barr virus
Akiko Yamada, Rieko Arakaki, Masako Saito, Takaaki Tsunematsu, Yasusei Kudo and Naozumi Ishimaru : Role of regulatory T cell in the pathogenesis of inflammatory bowel disease., World Journal of Gastroenterology : WJG, Vol.22, No.7, 2195-2205, Feb. 2016.
(Summary)
Regulatory T (Treg) cells play key roles in various immune responses. For example, Treg cells contribute to the complex pathogenesis of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis during onset or development of that disease. Many animal models of IBD have been used to investigate factors such as pathogenic cytokines, pathogenic bacteria, and T-cell functions, including those of Treg cells. In addition, analyses of patients with IBD facilitate our understanding of the precise mechanism of IBD. This review article focuses on the role of Treg cells and outlines the pathogenesis and therapeutic strategies of IBD based on previous reports.
Rieko Arakaki, Akiko Yamada, Yasusei Kudo, Yoshio Hayashi and Naozumi Ishimaru : Mechanism of Activation-Induced Cell Death of T Cells and Regulation of FasL Expression., Critical Reviews in Immunology, Vol.34, No.4, 301-314, May 2014.
(Summary)
Activation-induced cell death (AICD) of T cells is a process for regulating the peripheral immune system. The fate of a T cell is controlled by numerous signals derived from various stimuli, such as antigens, cytokines, and chemokines. In healthy humans, overactivated or autoreactive T cells are harmful and are eliminated to maintain the immune system. AICD in T cells by Fas/FasL-mediated apoptosis is triggered by the switch from life to death through several signaling molecules. The control or distribution of Fas or FasL expression largely affects AICD of T cells. Although autoimmune diseases are considered to be induced by multiple factors, an impaired immune system with AICD by Fas/FasL-mediated apoptosis leads to the onset or development of autoimmunity. Based on published reports, this review describes the regulatory mechanisms involved in AICD of T cells by Fas/ FasL-mediated apoptosis and the associations between AICD and autoimmunity in humans and animal models.
Shinji Iizuka, Naozumi Ishimaru and Yasusei Kudo : Matrix metalloproteinases: the gene expression signatures of head and neck cancer progression., Cancers, Vol.6, No.1, 396-415, Feb. 2014.
(Summary)
Extracellular matrix degradation by matrix metalloproteinases (MMPs) plays a pivotal role in cancer progression by promoting motility, invasion and angiogenesis. Studies have shown that MMP expression is increased in head and neck squamous cell carcinomas (HNSCCs), one of the most common cancers in the world, and contributes to poor outcome. In this review, we examine the expression pattern of MMPs in HNSCC by microarray datasets and summarize the current knowledge of MMPs, specifically MMP-1, -3, -7 -10, -12, -13, 14 and -19, that are highly expressed in HNSCCs and involved cancer invasion and angiogenesis.
Akiko Yamada, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : Targeting IL-1 in Sjögren's syndrome., Expert Opinion on Therapeutic Targets, Vol.17, No.4, 393-401, Jan. 2013.
(Summary)
Introduction: IL-1 plays key roles in the biological functions of various cells. In particular, many roles of IL-1 in the immune system have been discovered by numerous studies. This review focuses on the association of IL-1 with the pathogenesis of autoimmunity. Areas covered: An overview of the biological functions of the IL-1 family and the IL-1 receptors (IL-1Rs), including the maintenance of systemic or local homeostasis, and the signaling pathway through IL-1/IL-1R in various immune systems are described. Several functions of IL-1 in the pathogenesis of Sjögren's syndrome (SS) have been demonstrated with a focus on the immune responses and target tissues in SS. In addition to the role of IL-1 in the immune responses in SS, the function of IL-1 in ocular mucosa lesions in SS has been described. Lastly, there is an overview of possible therapeutic strategies for IL-1 inhibition in SS. Expert opinion: IL-1 plays critical roles in the onset and development of SS by controlling systemic or local immune responses and maintaining the survival and mucosal defense of target epithelial cells. The inhibition of the pathogenic functions of IL-1 may be beneficial for treating SS.
Yasusei Kudo, S B S M Siriwardena, H Hatano, I Ogawa and Takashi Takata : Periostin: novel diagnostic and therapeutic target for cancer., Histology and Histopathology, Vol.22, No.10, 1167-1174, Oct. 2007.
(Summary)
Periostin is a secreted protein that shares a structural homology to the axon guidance protein fasciclin I (FAS1) in insects and was originally named as osteoblast-specific factor-2 (Osf2). Periostin is particularly highly homologus to Betaig-h3, which promotes cell adhesion and spreading of fibroblasts. It has recently been reported that Periostin was frequently overexpressed in various types of human cancers. Although the detailed function of Periostin is still unclear, Periostin-integrin interaction through FAS1 domain is thought to be involved in tumor development. In addition, Periostin stimulates metastatic growth by promoting cancer cell survival, invasion and angiogenesis. Therefore, Periostin can be a useful marker to predict the behavior of cancer. This review summarizes the recent understanding of Periostin roles in tumor development and speculates on the usefulness of Periostin as a therapeutic and diagnostic target for cancer.
(Tokushima University Institutional Repository: 113592, PubMed: 17616943, Elsevier: Scopus)
Proceeding of International Conference:
1.
Yasusei Kudo : Classification of oral cancer by gene expression pattern and its application for treatment strategy, Head and Neck oncological personalized outcome by artificial intelligence genomic analysis, Oct. 2024.
2.
Yasusei Kudo : Molecular mechanism of Oral cancer progression, 22ST ANNUAL MEETING OF KOREAN ASSOCIATION OF ORAL SCIENCE, Nov. 2023.
3.
Yasusei Kudo : The Mechanism on invasion and metastasis of Oral Cancer, International Conference on Craniofacial Pathology & Biology, Oct. 2022.
4.
Natsumi Fujiwara, Hiromichi Yumoto, Keiji Murakami, Yasusei Kudo, Hiromi Nakae, Katsuhiko Hirota, Kazumi Ozaki and Yoichiro Miyake : 2-methacryloyloxyethyl-phosphorylcholine (MPC)-polymer suppresses the adherence of oral bacteria, 2018 IADR/PER General Session (ExCel London Convention Center, London, England) 25-28th July, 2018, Jul. 2018.
5.
Takaaki Tsunematsu, Naozumi Ishimaru and Yasusei Kudo : APC/CCdh1-mediated degradation of Borealin triggers differentiation of pluripotent stem cells., FASEB meeting Ubiquitin and Cellular Regulation, Snowmass Village, CO, USA, May 2018.
6.
Kunihiro Ohtsuka, Akiko Yamada, Masako Saito, Aya Ushio, Takaaki Tsunematsu, Rieko Arakaki, Yasusei Kudo, Hidehiro Kishimmoto and Naozumi Ishimaru : Analysis of follicular helper T cells in a mouse model for Sjogren's Syndorome., 11th International Congress of Autoimmunity, Lisbon, May 2018.
7.
Aya Ushio, Rieko Arakaki, Kunihiro Ohtsuka, Yasusei Kudo and Naozumi Ishimaru : CCL22Producing Resident Macrophages Enhances InflaMMation in Salivary Glands of Sjogren's Syndorome., 11th International Congress of Autoimmunity, Lisbon, May 2018.
8.
Rieko Arakaki, Aya Ushio, Kunihiro Ohtsuka, Yasusei Kudo and Naozumi Ishimaru : NF-kB2 Controls the Migratory of Memory T cells to the Target Tissues in a Mouse Model of Sjogren's Syndorome by Regulating Expression of CXCR4., 11th International Congress of Autoimmunity, Lisbon, May 2018.
9.
Naozumi Ishimaru, Mie Kurosawa, Rieko Arakaki, Aya Ushio, otsuka kunihiro and Yasusei Kudo : Contributions of CXCL12 and its receptor to the T cell autoimmune response in a Sjögren's syndrome murine model., 14th International Symposium on Sjögren's Syndrome, Washington, D.C., Apr. 2018.
10.
Takaaki Tsunematsu, Naozumi Ishimaru and Yasusei Kudo : Chromosome passenger complex protein,Borealin is regulated by APC/C Cdh1 ubiquitin ligase complex, Cold Spring Harbor Laboratory Meeting:The Ubiquitin Family, New York, Apr. 2017.
11.
Takaaki Tsunematsu, Naozumi Ishimaru and Yasusei Kudo : The APC/C-Cdh1-Borealin axis has critical role in the maintenance of undifferentiated state in embryonal carcinoma cells, 8th International Conference SUMO, Ubiquitin, UBL Proteins- Implications for Human Diseases, Shanghai, Oct. 2016.
12.
Akiko Yamada, Aya Ushio, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : Impaired Expansion of Regulatory T cells in a Neonatal Thymectomy-induced Autoimmune Mouse Model, ICI2016, Melbourne, Aug. 2016.
13.
Masako Saito, Kunihiro Ohtsuka, Aya Ushio, Mie Kurosawa, Akiko Yamada, Yasusei Kudo, Rieko Arakaki and Naozumi Ishimaru : Abnormal germinal center(GC)reaction in autoimmunity., ICI2016, Melbourne, Aug. 2016.
14.
Yasusei Kudo, Takaaki Tsunematsu and Naozumi Ishimaru : Chromosome passenger complex protein,Borealin is regulated by APC/C-Cdh1 ubiquitin ligase complex, FASEB Ubiquitin & Cellular Regulation, Montana, Jun. 2016.
15.
Yasusei Kudo, 常松 貴明 and Naozumi Ishimaru : Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and CDT1 in mitosis., 7th International Conference SUMO,Ubiquitin,UBL Proteins:Implications for Human Diseases, Shanghai, May 2014.
16.
Yasusei Kudo, 常松 貴明 and Naozumi Ishimaru : Geminin regulates pre-replicative complex formation though the stabilization of CDT1 in mitosis., American Association for Cancer Reseach, San Diego, Apr. 2014.
17.
Akihiko Iwasa, Rieko Arakaki, Akiko Yamada, Eiji Tanaka, Yasusei Kudo and Naozumi Ishimaru : Pathologenesis of Sjogren's syndrome through Aromatase and adipose tissue., International Congress on Autoimmunity, Niece, Mar. 2014.
18.
Tomoyuki Kondo, Akiko Yamada, Rieko Arakaki, Takaaki Tsunematu, Yasusei Kudo and Naozumi Ishimaru : Analysis of the regulatory mechanism for tumor immunity by using autoimmune lpr mice., International Congress on Autoimmunity, Niece, Mar. 2014.
19.
Koichi Yamada, Akihiko Iwasa, Tomoyuki Kondo, Mie Kurosawa, Rieko Arakaki, Akiko Yamada, Yasusei Kudo, Y Taquahashi, A Takagi, J Kanno and Naozumi Ishimaru : Invivo effect of multi-wall carbon nanotubes on immune system., 6th International Symposium on Nanotechnology,Occupational and Environmental system., Nagoya, Nov. 2013.
20.
Yosuke Shikama, Naozumi Ishimaru, Yasusei Kudo, Yukiko Bandou, Nanako Aki, Yoshio Hayashi and Makoto Funaki : High Levels of Free Fatty Acids May Advance the Severity of Primary Sjögrens Syndrome, Diabetes, Vol.62, No.Supplement 1, A166, Jul. 2013.
21.
Nobuyuki Kuribayashi, Daisuke Uchida, Yasusei Kudo, Makoto Kinouchi, Tetsuya Tamatani, Hirokazu Nagai and Youji Miyamoto : Expression and function of CXCR4 in human salivary gland cancers, American Associattion for Cancer Research Annual Meeting 2013, Apr. 2013.
22.
Yasusei Kudo, Takaaki Tsunematsu and Takashi Takata : Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and CDT1 in mitosis., The Cell Cycle, New York, May 2012.
23.
Yasusei Kudo, Takaaki Tsunematsu and Takashi Takata : Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and CDT1 in mitosis., The Cell Cycle, May 2012.
Proceeding of Domestic Conference:
1.
siqi chen, Natsumi Fujiwara, Yasuhiro Mouri and Yasusei Kudo : Oral cancer microenvironment for promoting the biofilm formation of Fusobacterium nucleatum, 第83回日本癌学会学術総会, Sep. 2024.
2.
Yasusei Kudo : Classification and treatment strategies for oral cancer based on gene expression patterns, 第78回日本口腔科学会学術集会, Jul. 2024.
3.
Wenhua Shao, Yasuhiro Mouri, Takeshi Oya and Yasusei Kudo : The role of Fat1 gene mutation in the development of maxillofacial anomalies, 第113回日本病理学会総会, Mar. 2024.
4.
Wenhua Shao, Yasuhiro Mouri, Takeshi Oya and Yasusei Kudo : The novel function of Fat1 gene mutation in the development of maxillofacial anomalies, 第129回日本解剖学会総会・全国学術集会, Mar. 2024.
Jin Shengjian, Takaaki Tsunematsu, Taigo Horiguchi, Yasuhiro Mouri, Wenhua Shao, Keiko Miyoshi, Noriko Mizusawa, Hagita Hiroko, Sarubo Motoharu, Yoshida Kayo, Kaya Yoshida, Natsumi Fujiwara, Kazumi Ozaki, Naozumi Ishimaru and Yasusei Kudo : The role of deubiquitinating enzyme, OTUB1 in head and neck squamous cell carcinoma (HNSCC) progression, 第82回日本癌学会学術集会, Sep. 2023.
7.
Sarubo Motoharu, Moromizato Akira, Yamada Azusa, Wenhua Shao, Jin Shengjian, Yasuhiro Mouri and Yasusei Kudo : The role of TGFBIin partial-EMT induction of head and neck squamous cell carcinoma, 第82回日本癌学会学術総会, Sep. 2023.
8.
sarubo motoharu and Yasusei Kudo : TGFBI-TAGLN axis regulates cancer stem cell properties in head and neck squamous cell carcinoma, 第65回歯科基礎医学会学術集会, Sep. 2023.
北島 正二朗 and Yasusei Kudo : がん幹細胞の代謝特性と幹細胞性維持メカニズム, 第65回歯科基礎医学会学術大会, Sep. 2023.
12.
YOSHIDA Kayo, Kaya Yoshida, Mariko Seyama, MEKATA Mana, Natsumi Fujiwara, Noriko Mizusawa, Yasuhiro Mouri, Yasusei Kudo and Kazumi Ozaki : 歯周病原菌由来細胞外小胞を介した肺炎発症メカニズムの解明, 第66回春季日本歯周病学会学術大会, May 2023.
13.
Yoshiko Yamamura, Yasuhiro Mouri, Kumiko Kamada, Naito Kurio, Keiko Kudoh, Yasusei Kudo and Youji Miyamoto : 唾液腺の発達・再生におけるNrepの役割, 第77回NPO法人日本口腔科学会学術集会, May 2023.
14.
Wenhua Shao, Yasuhiro Mouri and Yasusei Kudo : The role of Fat1 in maxillofacial development, 第112回 日本病理学会総会, Apr. 2023.
15.
Jin Shengjian, Takaaki Tsunematsu, Taigo Horiguchi, Yasuhiro Mouri, Wenhua Shao, Keiko Miyoshi, Noriko Mizusawa, Hiroko Hagita, YOSHIDA Kayo, Kaya Yoshida, Natsumi Fujiwara, Kazumi Ozaki, Naozumi Ishimaru and Yasusei Kudo : The role of Deubiquitinating enzyme, OTUB1 in head and neck squamous cell carcinoma (HNSCC) progression, 第61回四国歯学会, Mar. 2023.
Wenhua Shao, Yasuhiro Mouri and Yasusei Kudo : The novel function of Fat1 in maxillofacial development, 第45回日本分子生物学会年会, Dec. 2022.
18.
Sarubou Motoharu, Wenhua Shao, Yasuhiro Mouri and Yasusei Kudo : The role of Transforming growth factor beta-induced (TGFβ1) in partial-EMT induction of Head and Neck squamous cell carcinoma, 第45回日本分子生物学会年会, Dec. 2022.
19.
Wenhua Shao, Yasuhiro Mouri and Yasusei Kudo : The novel function Fat1 in maxillofacial development, 第45回日本分子生物学会年会, Nov. 2022.
Yasusei Kudo : 染色体パッセンジャー複合体による多能性幹細胞の未分化能維持機構, 第12回RNAi研究会, Aug. 2021.
39.
Kunihiro Otsuka, Akiko Yamada, Masako Saito, Aya Ushio, Mami Sato, Satoru Kisoda, Wenhua Shao, Takaaki Tsunematsu, Yasusei Kudo, Rieko Arakaki and Naozumi Ishimaru : Achaete-Scute Homologue 2-Regulated Follicular Helper T Cells Promote Autoimmunity in a Murine Model for Sjögren Syndrome., 第32回日本臨床口腔病理学会 奨励賞(実験病理分野), Aug. 2021.
40.
Takaaki Tsunematsu, KITAGAWA Takumi, Yasusei Kudo and Naozumi Ishimaru : 口腔扁平上皮癌の進展におけるPeriostinスプライシングバリアントの新たな役割, 第75回日本口腔科学会学術集会, May 2021.
41.
Yoshiko Yamamura, Yasusei Kudo, Yasuhiro Mouri, Wenhua Shao, 横田 美保 and Youji Miyamoto : 腺房細胞の再生に関わる遺伝子ネットワークの同定, 第75回日本口腔科学会学術集会, May 2021.
42.
Kisoda Satoru, Wenhua Shao, Jin Shengjian, Takaaki Tsunematsu, Naozumi Ishimaru and Yasusei Kudo : Development of a novel prognostic prediction system for head and neck squamous cell carcinoma, 第79回日本癌学会学術総会, Oct. 2020.
Yoshiko Yamamura, Go Ohe, Yasusei Kudo, Naito Kurio, 鎌田 久美子, Naoyuki Fukuda, Keiko Kudoh, Takamitsu Mano, Naozumi Ishimaru and Youji Miyamoto : 口腔扁平苔癬からの癌化が疑われた口腔扁平上皮癌の4例, 第38回日本口腔腫瘍学会総会・学術大会, Jan. 2020.
47.
Kumiko Kamada, Naito Kurio, Go Ohe, Keiko Kudoh, Yasusei Kudo, Takamitsu Mano, Naozumi Ishimaru and Youji Miyamoto : 口底に発生した類基底扁平上皮癌の1例, 第38回日本口腔腫瘍学会総会・学術大会, Jan. 2020.
48.
Aya Ushio, Rieko Arakaki, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : Analysis of pulmonary lesions in a murlne model of sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2019.
49.
Mami Sato, Rieko Arakaki, Aya Ushio, Yasusei Kudo and Naozumi Ishimaru : Effect of mulyi-wall carbon nanotube exposure on pulmonary immune cells at the early stage., Proceedings of the Japanese Society for Immunology, Dec. 2019.
50.
Kumiko Kamada, Naito Kurio, Go Ohe, Keiko Kudoh, Yoshiko Yamamura, Naoyuki Fukuda, Takamitsu Mano, Yasusei Kudo, Naozumi Ishimaru and Youji Miyamoto : 上顎歯肉に発生したMicorocystic adnexal carcinoma(MAC)の1例, 第64回日本口腔外科学会総会・学術大会, Oct. 2019.
51.
Aya Ushio, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : 自己免疫疾患モデルにおける標的臓器常在型マクロファージの役割, Japanese Journal of Oral Biology, Oct. 2019.
52.
Naito Kurio, 鎌田 久美子, Go Ohe, 横田 美保, Yoshiko Yamamura, Keiko Kudoh, Yasusei Kudo, Takamitsu Mano, Naozumi Ishimaru and Youji Miyamoto : 歯肉腫瘤により白血病化が明らかとなった骨髄異形成症候群の1例, 第67回 日本口腔科学会中国・四国地方部会, Oct. 2019.
Aya Ushio, Rieko Arakaki, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : The new therapeutic strategy targeting chemokine in Sjogren's Syndorome., 日本RNAi研究会, Aug. 2019.
57.
Takaaki Tsunematsu, Naozumi Ishimaru and Yasusei Kudo : The maintenance of pluripotency by chromosome passenger complex in pluripotent stem cells., 日本RNAi研究会, Aug. 2019.
58.
Takaaki Tsunematsu, Naozumi Ishimaru and Yasusei Kudo : 染色体パッセンジャー複合体によるAurora-B活性を介した多能性幹細胞の未分化能維持機構, 第16回日本病理学会カンファレンス, Aug. 2019.
59.
Satoru Kisoda, Wenhua Shao, Aya Ushio, Mami Sato, Rieko Arakaki, Naozumi Ishimaru and Yasusei Kudo : 口腔癌におけるpartial-EMTに関する遺伝子の悪性度への関与, 第38回分子病理研究会, Jul. 2019.
60.
Aya Ushio, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : シェーグレン症候群モデルマウスの唾液腺病態形成におけるマクロファージの役割, 第38回分子病理研究会, Jul. 2019.
Aya Ushio, Rieko Arakaki, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : シェーグレン症候群モデルマウスの標的組織マクロファージが病態形成に及ぼす影響, 第18回四国免疫フォーラム, Jun. 2019.
63.
Haruna Matsukura, Aya Ushio, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : シェーグレン症候群疾患モデルにおける胚病変の解析, 第108回日本病理学会総会, May 2019.
64.
Aya Ushio, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : シェーグレン症候群病態形成におけるCCL22産生マクロファージの役割, 第108回日本病理学会総会, May 2019.
65.
Takaaki Tsunematsu, Hidehiko Kawai, Naozumi Ishimaru, Willium C Earnshaw, Michele Pagano and Yasusei Kudo : 染色体パッセンジャー複合体による多能性幹細胞の未分化能維持機構, 第36回染色体ワークショップ, Jan. 2019.
(Keyword)
cell cycle / induced pluripotent stem cells
66.
Rieko Arakaki, Nakayama Shinichiro, Aya Ushio, Otsuka Kunihiro, Kisoda Satoshi, Takaaki Tsunematsu, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : The role of the cleaved from IL-33 in pathogenesis of Sjogren's syndorome(SS), Proceedings of the Japanese Society for Immunology, Dec. 2018.
67.
Aya Ushio, Rieko Arakaki, Kunihiro Ohtsuka, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : CCL22-producing macrophages promote T cell autoimmunity in the target organ of Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2018.
68.
Kunihiro Ohtsuka, Akiko Yamada, Masako Saito, Aya Ushio, Satoru Kisoda, Takaaki Tsunematsu, Yasusei Kudo, Rieko Arakaki and Naozumi Ishimaru : A crucial role of follicular helper T cells in autoimmunity of a mouse model for Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2018.
Rieko Arakaki, Aya Ushio, Kunihiro Ohtsuka, Yasusei Kudo and Naozumi Ishimaru : 全身吸入暴露による多層化カーボンナノチューブの肺胞マクロファージへの影響, Proceedings of the Japanese Society of Pathology, Vol.107, Jun. 2018.
79.
Shinichiroh Nakayama, Rieko Arakaki, Aya Ushio, Kunihiro Ohtsuka, Takaaki Tsunematsu, Yasusei Kudo and Naozumi Ishimaru : シェーグレン症候群モデルマウス唾液腺におけるIL-33の発現とその役割, Proceedings of the Japanese Society of Pathology, Vol.107, Jun. 2018.
80.
Saki Saijoh, Kunihiro Ohtsuka, Takaaki Tsunematsu, Kunihiro Ohtsuka, Aya Ushio, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : Emi1の過剰発現による人工口腔癌幹細胞の作成, Proceedings of the Japanese Society of Pathology, Vol.107, Jun. 2018.
81.
Yukino Numata, Kunihiro Ohtsuka, Akiko Yamada, Aya Ushio, Takaaki Tsunematsu, Yasusei Kudo, Rieko Arakaki and Naozumi Ishimaru : シェーグレン症候群疾患モデルにおけるNotchシグナルの役割, Proceedings of the Japanese Society of Pathology, Vol.107, Jun. 2018.
82.
Kunihiro Ohtsuka, Akiko Yamada, Masako Saito, Aya Ushio, Takaaki Tsunematsu, Yasusei Kudo, Rieko Arakaki and Naozumi Ishimaru : シェーグレン症候群疾患モデルの自己免疫病変における濾胞ヘルパーT細胞の役割, Proceedings of the Japanese Society of Pathology, Vol.107, Jun. 2018.
Aya Ushio, Rieko Arakaki, Akiko Yamada, Kunihiro Ohtsuka, Yasusei Kudo and Naozumi Ishimaru : CCL22-producing resident macrophages enhancesnautoimmune lesions in a mouse model of Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Vol.46, 119, Dec. 2017.
85.
Kunihiro Ohtsuka, Akiko Yamada, Aya Ushio, Mie Kurosawa, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : Analysis of follicular helper T cells in a mouse model for Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Vol.46, 81, Dec. 2017.
Takaaki Tsunematsu, Yasusei Kudo, Akiko Yamada, Rieko Arakaki, Hirohisa Ogawa, Koichi Tsuneyama and Naozumi Ishimaru : 胎児性癌細胞におけるユビキチンプロテアソーム経路による未分化性維持機構, Proceedings of the Japanese Society of Pathology, Vol.106, No.1, 356, Mar. 2017.
100.
Rieko Arakaki, Kohichi Yamada, Aya Ushio, Mie Kurosawa, Kunihiro Ohtsuka, Masako Saito, Takaaki Tsunematsu, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : Immunological and toxicological effect of multi-wall carbon nanotubes by whole body inhalation exposure in B6 mice, 第45回日本免疫学会学術集会, Vol.45, Dec. 2016.
101.
Akiko Yamada, Rieko Arakaki, Aya Ushio, Takaaki Tsunematsu, Yasusei Kudo and Naozumi Ishimaru : 1)Impaired Expansion of Regulatory T cells in a Murine model of Neonatal Thymectomy-induced Sjogrens Syndrome, 第45回日本免疫学会学術集会, Vol.45, Dec. 2016.
102.
Kunihiro Ohtsuka, Masako Saito, Mie Kurosawa, Aya Ushio, Akiko Yamada, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : Analysis of follicular helper T cells in a mouse model for Sjogren's syndrome., 第45回日本免疫学会学術集会, Vol.45, Dec. 2016.
103.
Aya Ushio, Rieko Arakaki, Masako Saito, Akiko Yamada, Kunihiro Ohtsuka, Mie Kurosawa, Satoko Kujiraoka, Yasusei Kudo and Naozumi Ishimaru : Analysis of macrophages in the pathogenesis of a murine model for Sjogren's syndrome., 第45回日本免疫学会学術集会, Vol.45, Dec. 2016.
Rieko Arakaki, Takaaki Tsunematsu, Akiko Yamada, Masako Saito, Yasusei Kudo and Naozumi Ishimaru : 全身吸入暴露による多層化カーボンナノチューブの免疫システムへの影響, 第105回日本病理学会総会, Vol.105, No.1, May 2016.
112.
Aya Ushio, Masako Saito, Akiko Yamada, Kunihiro Ohtsuka, Mie Kurosawa, Satoko Kujiraoka, Yasusei Kudo and Naozumi Ishimaru : シェーグレン症候群モデルマウスの病態形成におけるマクロファージの役割, 第105回日本病理学会総会, Vol.105, No.1, May 2016.
113.
Satoko Kujiraoka, Yasusei Kudo, Takaaki Tsunematsu, Tomoyuki Kondoh, Aya Ushio, Kunihiro Ohtsuka, Akiko Yamada, Rieko Arakaki and Naozumi Ishimaru : 顎骨中心性明細胞性腫瘍からの細胞株の樹立とその性状, 第105回日本病理学会総会, Vol.105, No.1, May 2016.
114.
Takaaki Tsunematsu, Yasusei Kudo, Akiko Yamada, Rieko Arakaki, Hirohisa Ogawa, Hisanori Uehara, Naozumi Ishimaru and Koichi Tsuneyama : 染色体パッセンジャー複合体タンパク質Borealinのユビキチン分解の意義とその癌化への関与, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 548, Apr. 2016.
115.
Masako Saito, Rieko Arakaki, Kunihiro Ohtsuka, Kohichi Yamada, Yasusei Kudo and Naozumi Ishimaru : Biological effect of Multi-Walled Carbon Nanotubes(MWCNTs)on imune system., Proceedings of the Japanese Society for Immunology, Nov. 2015.
116.
Rieko Arakaki, Aya Ushio, Mie Kurosawa, Kunihiro Ohtsuka, Akiko Yamada, Masako Saito, Takaaki Tsunematsu, Yasusei Kudo and Naozumi Ishimaru : Analysis of function of macrophages in murine models of Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Nov. 2015.
117.
Mie Kurosawa, Akiko Yamada, Rieko Arakaki, Masako Saito, Takaaki Tsunematsu, Yasusei Kudo and Naozumi Ishimaru : Migratory activity of memory T cells in aly/aly mice., Proceedings of the Japanese Society for Immunology, Nov. 2015.
Yasusei Kudo : Collapse of the Cell Cycle Regulation Controlled by the Ubiquitin-mediated Proteolysis Causes Carcinogenesis, Invited LectureRGJ-Ph.D. Congress XVI, Jun. 2015.
122.
Takaaki Tsunematsu, Yasusei Kudo, Tomoyuki Kondoh, Aya Ushio, Satoko Kujiraoka, Akiko Yamada, Rieko Arakaki and Naozumi Ishimaru : 染色体パッセンジャー複合体タンパク質Borealinのユビキチン分解とその癌化への関与, 日本病理学会会誌, Vol.104, No.1, 504, May 2015.
Aya Ushio, Rieko Arakaki, Tomoyuki Kondoh, Satoko Kujiraoka, Takaaki Tsunematsu, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : Analysis of macrophages in the pathogenesis of a murine for Sjogren's syndorome., 日本病理学会会誌, Vol.104, No.1, 450, Apr. 2015.
Aya Ushio, Rieko Arakaki, Mie Kurosawa, Tomoyuki Kondoh, Satoko Kujiraoka, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : Analysis of macrophages in the pathogenesis of murine models for Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2014.
129.
Rieko Arakaki, Aya Ushio, Kohichi Yamada, Mie Kurosawa, Satoko Kujiraoka, Tomoyuki Kondoh, 常松 貴明, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : Influence of multi-wall carbon nanotubes on immune system in nomal mice and MRL/lpr mice., Proceedings of the Japanese Society for Immunology, Dec. 2014.
130.
Mie Kurosawa, Akiko Yamada, Rieko Arakaki, Tomoyuki Kondoh, 常松 貴明, Yasusei Kudo, Satoko Kujiraoka, Aya Ushio and Naozumi Ishimaru : A novel role of CXCR7 in memory T cells of a murine model for Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2014.
Yosuke Shikama, Yasusei Kudo, Naozumi Ishimaru and Makoto Funaki : 飽和脂肪酸が歯周病の病態形成に関与する可能性(Possibility of involvement of saturated fatty acids in pathogenesis of periodontitis), Journal of Oral Biosciences Supplement, Vol.2014, 161, Sep. 2014.
134.
Tomoyuki Kondoh, 常松 貴明, Mie Kurosawa, Satoko Kujiraoka, Aya Ushio, Akiko Yamada, Rieko Arakaki, Yasusei Kudo and Naozumi Ishimaru : Analysis of regulatory mechanism of tumor immunity using an animal model for autoimmunity., 第25回日本臨床口腔病理学会, Aug. 2014.
135.
Aya Ushio, Rieko Arakaki, Mie Kurosawa, Tomoyuki Kondoh, Satoko Kujiraoka, 常松 貴明, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : Analysis of macrophages in the pathogenesis of Sjogren's syndrome using murine models., 第25回日本臨床口腔病理学会, Aug. 2014.
136.
Satoko Kujiraoka, Yasusei Kudo, 常松 貴明, Tomoyuki Kondoh, Aya Ushio, Mie Kurosawa, Akiko Yamada, Rieko Arakaki and Naozumi Ishimaru : The role of splicing variants of periostin in oral cancer cells., 第25回日本臨床口腔病理学会, Aug. 2014.
Mie Kurosawa, Naozumi Ishimaru, Rieko Arakaki, Akiko Yamada, Yasusei Kudo and Tomoyuki Kondoh : Anovel role of CXCR7 in controlling autoreactive T cells of a murine model for Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2013.
145.
Akihiko Iwasa, Mie Kurosawa, Rieko Arakaki, Akiko Yamada, Eiji Tanaka, Yasusei Kudo and Naozumi Ishimaru : Relationship between aromatase-related obesity and autoimmunity in Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2013.
146.
Rieko Arakaki, Hiroshi Eguchi, Akiko Yamada, Yasusei Kudo, Yoshinori Mitamura, Yoshio Hayashi and Naozumi Ishimaru : Eye drop administration of rebamipide is effective to a dry eye symptom in a model mice of Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2013.
147.
Yasusei Kudo, 常松 貴明 and Naozumi Ishimaru : Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and CDT1 in mitosis., 第36回日本分子生物学会年会, Dec. 2013.
Tsunematsu Takaaki and Yasusei Kudo : Chromosome passenger complex protein,Borealin is regulated by APC/CCdh1 ubiquitin ligase complex, 第35回Naito Conference, Jul. 2013.
152.
Yasusei Kudo, Takaaki Tsunematsu and Naozumi Ishimaru : Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and Cdt1 in mitosis, 第35回Naito Conference, Jul. 2013.
Tomoyuki Kondoh, Yasusei Kudo and Naozumi Ishimaru : 自己免疫疾患モデルを用いた腫瘍免疫システムの解析, Journal of The Japanese Stomatological Society, Vol.67, 200, May 2013.
160.
Rieko Arakaki, Hiroshi Eguchi, Akiko Yamada, Yasusei Kudo, Yoshinori Mitamura, Yoshio Hayashi and Naozumi Ishimaru : An Effective Therapy of Ocular Lesions in a Murine Model for Sjogren's Syndorome by Eye Drop Administration of Rebamipide., Proceedings of the Japanese Society for Immunology, Dec. 2012.
161.
Mie Kurosawa, Akiko Yamada, Rieko Arakaki, Tomoyuki Kondo, Yasusei Kudo and Naozumi Ishimaru : Analysis of infiltrating immune cells in the target tissues of murine models for Sjogren's syndorome., Proceedings of the Japanese Society for Immunology, Dec. 2012.
162.
Akiko Yamada, Rieko Arakaki, Mie Kurosawa, Tomoyuki Kondo, Yasusei Kudo, Yoshio Hayashi and Naozumi Ishimaru : Functional defect of Foxp3+Treg cells in Sjogren's syndrome., Proceedings of the Japanese Society for Immunology, Dec. 2012.
163.
Akihiko Iwasa, Rieko Arakaki, Akiko Yamada, Eiji Tanaka, Yasusei Kudo and Naozumi Ishimaru : The dysfunction of the aromatase worsens the pathogenesis of Sjogren's syndrome., Proceedings of the Japanese Society for Immunology, Dec. 2012.
Yasusei Kudo, 常松 貴明, 近藤 智之, Naozumi Ishimaru and Takashi Takata : Chromosome passenger complex protein,Borealin is regulated by APC/C-Cdh1 ubiquitin ligase complex, Proceedings of the Japanese Cancer Association, Sep. 2012.
167.
Takaaki Tsunematsu, Yasusei Kudo and Takashi Takata : 細胞分裂期におけるDNA複製抑制因子Gemininのユビキチン分解抑制機構とその新たな役割, Japanese Journal of Oral Biology, Sep. 2012.
PT Nguyen, Toshihiro Inubushi, 常松 貴明, Yasusei Kudo, Nobuyuki Kamata, 小川 郁子 and Takashi Takata : FGFR-1 inhibitor PD173074 induces mesenchymal-epithelial tramsition through suppression of AP-1 in Head and Neck Squamous Cell Carcinoma, 第23回日本臨床口腔病理学会, Sep. 2012.
174.
Tsunematsu Takaaki, Yasusei Kudo and Takashi Takata : Aurora-A induces the stabilization of DNA licensing inhibitor,Geminin, 第23回日本臨床口腔病理学会総会・学術大会, Aug. 2012.
175.
Akihiko Iwasa, Rieko Arakaki, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru : A critical role of aromatase in the pathogenesis of Sjogren's syndrome, 第31回分子病理学研究会, Jul. 2012.
176.
安藤 俊範, 常松 貴明, Yasusei Kudo, 小川 郁子, Mutsumi Miyauchi and Takashi Takata : The role as tumor suppressor gene and the expression of Ameloblastin in osteosarcoma, 第66回日本口腔科学会, May 2012.
siqi chen and Yasusei Kudo : Oral cancer microenvironment for the growth of Fusobacteirum nucleatum, 2023 Tokushima Bioscience Retreat, Sep. 2023.
2.
jian sheng jin and Yasusei Kudo : Involvement of OTUB1-YAP1 axis in driving malignant behaviors of head and neck squamous cell carcinoma, 2023 Tokushima Bioscience Retreat, Sep. 2023.
Elucidation of the molecular mechanism of maxillofacial hypoplasia caused by FAT1 gene mutation (Project/Area Number: 22K19629 )
Investigation of novel oral cancer-specific molecular targets based on genetic diversity (Project/Area Number: 23K24546 )
Investigation of the pathophysiology of oral cancer caused by Fusobacterium nucleatum infection (Project/Area Number: 22K10342 )
The identification of genes involved in the maintenance and regeneration of salivary gland stem / progenitor cells and application to new xerostomia treatment (Project/Area Number: 22K10121 )
Investigation of novel molecular targets for oral cancer stem cells and establishment of novel oral cancer treatment strategy (Project/Area Number: 21KK0162 )
Clarification of the mechanism on differentiation of pluripotent stem cells by Aurora-B and its application to regeneration therapy (Project/Area Number: 19K22718 )
Establishment of novel oral cancer stem cell model mimicking human oral cancer by reprogramming and insertion of gene mutation (Project/Area Number: 19H03853 )
Analysis of Pathogenesis of Autoimmunity through Communication between Organs (Project/Area Number: 19H01070 )
Molecular Mechanism of Autoimmune Germinal Center Reaction and a New Therapeutic Strategy for Autoimmunity (Project/Area Number: 18K19648 )
Elucidation of regulatory chemical messengers in oral cancer stem cell niche and its diagnostic and therapeutic application (Project/Area Number: 18H03000 )
Establishment of highly metastatic mice model of oral squamous cell carcinoma (Project/Area Number: 17K19761 )
Study on the generation of oral cancer stem cell and analysis of its nature (Project/Area Number: 17K19760 )
The development of preventives and therapeutics against systemic endothelial dysfunction induced by the periodontal inflammation and the effects of anesthetics to the induced endothelial dysfunction (Project/Area Number: 17K11910 )
Clarification of the mechanism of oral carcinogenesis by the defect of degradation of chromosome passenger complex protein (Project/Area Number: 16H05542 )
Analysis of autoimmunity caused by environmental factors~New pathogenesis of autoimmune disease~ (Project/Area Number: 16H02690 )
Explore for master regulator of EMT in oral cancer (Project/Area Number: 15K15740 )
The mechanism of tumorigenesis by disruption of the regulation of geminin proteolysis (Project/Area Number: 25670778 )
Mechanism of carcinogenesis by dysregulation of cell cycle via abnormal ubiquitin-mediated proteolysis (Project/Area Number: 23689074 )
The involvement and their molecular mechanism of microRNAs in the invasion of oral cancer (Project/Area Number: 23659858 )
Elucidation of invasive andmetastatic mechanism in oral cancer for application to molecular based diagnosisand gene therapy (Project/Area Number: 21249088 )
Oncogenic role of APC/C ubiquitin ligase inhibitor, Emi1 (Project/Area Number: 20689033 )
Histological and molecular biological study for standardization of pathological diagnosis of salivary gland tumors (Project/Area Number: 20592141 )
Study for degradation mechanism of a cell cycle regulator induced by Stress-activated MAP kinases (Project/Area Number: 20570126 )
Study on alteration of expression of genes and proteins related to development, progression and characteristic morphogenesis of salivary gland tumors (Project/Area Number: 15591935 )
Identification creation of bioactive sites of enamel proteins for developing a new therapy of periodontal tissue regeneration. (Project/Area Number: 14370583 )
Experimental pathological study on roles of chemokines in LPS-induced periodontal tissue destruction - Basic analysis on remedical effects of specific antibody against chemokine - (Project/Area Number: 12671773 )
Establishment of cementblast cell lines and periodontal ligament cell lines (Project/Area Number: 11470378 )
Experimental pathological study on roles of LPS-binding receptor CD14 in LPS-induced periodontal tissue destruction (Project/Area Number: 10671702 )
Analysis of Cell Cycle Regulators and Extracellular Matrices Associated with Cell Proliferation in Salivary Gland Tumors (Project/Area Number: 10671700 )
Development of dental implant with support of periodontal ligament (Project/Area Number: 10557159 )