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
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.
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.
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.
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.
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.
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.
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.
Yaping Ren, Wenhua Shao, Lijun Zuo, Wei Zhao, Haizhang Qin, Yingjie Hua, Dejie Lu, Chao Mi, Sien Zeng and Liao Zu : Mechanism of cadmium poisoning on testicular injury in mice., Oncology Letters, Vol.18, No.2, 1035-1042, 2019.
(Summary)
Cadmium is a heavy metal that is toxic to humans and the reproductive system. The present study aimed to investigate the mechanisms of cadmium-induced reproductive toxicity in a male Institute of Cancer Research mouse model of cadmium poisoning. Changes in luteinizing hormone receptor (LHR), 17α-hydroxylase and endothelial nitric oxide (NO) synthase (eNOS) expression levels were examined. A total of 24 male mice (4-week-old) were randomly divided into four groups (normal control group and low, medium and high cadmium groups) and subjected to gavage treatment with normal saline or cadmium-containing saline solutions for 8 weeks prior to sacrifice. To assess testicular injury, serum androgen levels were determined by ELISA, testicular tissue pathological changes were evaluated using hematoxylin and eosin staining. In addition, LHR, 17α-hydroxylase and eNOS expressions levels were examined by western blotting, and apoptosis was examined with a terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The results demonstrated that the severity of testes injury increased with cadmium concentration. In addition, LHR, 17α-hydroxylase and eNOS expression levels increased with low and medium concentrations of cadmium; however, they were decreased following treatment with high concentrations of cadmium. The results from the present study demonstrated that cadmium altered LHR, 17α-hydroxylase and eNOS expression levels in testicular stromal cells, which may impact testosterone synthesis. Furthermore, NO was suggested to be involved in cadmium-induced testicular injury by measurements of eNOS expression in testicular stromal cells.
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.
Haipeng Wang, Shengjian Jin, Huiling Lu, Sisi Mi, Wenhua Shao, Xiaoxv Zuo, Huangyi Yin, Sien Zeng, Fumio Shimamoto and Guangying Qi : Expression of survivin, MUC2 and MUC5 in colorectal cancer and their association with clinicopathological characteristics., Oncology Letters, Vol.14, No.1, 1011-1016, 2017.
(Summary)
Survivin is a bifunctional protein that suppresses apoptosis and regulates cell division, and is highly expressed in various cancer types. Mucins are high-molecular-weight, heavily glycosylated proteins. In the present study, the association between survivin, mucin 2 (MUC2) and MUC5 expression, and the clinicopathological features of colorectal cancer (CRC) were investigated. The immunohistochemistry and western blotting results demonstrated that survivin was highly expressed in CRC tissues and rarely expressed in normal colon tissues. Moreover, the overexpression of survivin and MUC5 was strongly associated with lymph node metastasis, poor cellular differentiation, advanced tumor stage and a poor prognosis in CRC. By contrast, low expression of MUC2 was significantly associated with lymph node metastasis, poor cellular differentiation and an advanced tumor stage in CRC. The results of the present study suggest that survivin, MUC2 and MUC5 levels may be associated with tumor progression and could be used to aid the early diagnosis and clinical characterization of CRC.
Chunbo Xia, Lin Zhu, Wenhua Shao, Sisi Mi, Sen Du, Lin Ye, Manjun Liu, YongJun Pang, Linlin Nong, Changwen Jiang, Hailu Zhao and Guangying Qi : The Effect of Hippocampal Cognitive Impairment and XIAP on Glucose and Lipids Metabolism in Rats., Cellular Physiology and Biochemistry, Vol.38, No.2, 609-618, 2016.
(Summary)
Cognitive impairment and hippocampal neuron apoptosis can cause glucose and lipids metabolic abnormalities, possibly by regulating gastrointestinal motility and AMPK expression in the liver. The changes in the function of XIAP, which is an anti-apoptotic protein in the hippocampus, may affect the metabolism of glucose and lipids.
(Keyword)
AMP-Activated Protein Kinases / Animals / Apoptosis / Blood Glucose / Cognition Disorders / Female / Gastrointestinal Motility / Glucose / Hippocampus / Lipid Metabolism / Lipids / Male / Rats, Sprague-Dawley / X-Linked Inhibitor of Apoptosis Protein
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
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.
Koichi Tsuneyama, Wenhua Shao and Mayuko Shimizu : Various type of hepatocellular adenomas occurred spontaneously in the liver of metabolic syndrome-associated steatohepatitis model, TSOD mice, AASLD The Liver meeting 2022, Nov. 2022.
Proceeding of Domestic Conference:
1.
Wenhua Shao : 徳島での私の生活, 第113回日本病理学会総会, Mar. 2024.
2.
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.
3.
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.
4.
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.
5.
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.
6.
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.
7.
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.
10.
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.
11.
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.
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.
18.
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.
19.
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.
20.
Wenhua Shao, Umeda Masaaki, Takaaki Tsunematsu, Kisoda Satoru and Naozumi Ishimaru : Novel periostin inform promotes invasion and metastasis in head and neck squamous cell carcinoma., 第109回 日本病理学会総会, Jul. 2020.
Wenhua Shao, Yuan Jin, Sisi Mi, Guangying Qi and Sien Zeng : The research of HCG in the proliferation , invasion and metastasis of colorectal carcinoma, 第38回分子病理研究会, Jul. 2019.
23.
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.