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en: Wnt/β-catenin signaling pathway in liver biology and tumorigenesis.

en: The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway that controls fundamental physiological and pathological processes by regulating cell proliferation and differentiation. The Wnt/β-catenin pathway enables liver homeostasis by inducing differentiation and contributes to liver-specific features such as metabolic zonation and regeneration. In contrast, abnormalities in the Wnt/β-catenin pathway promote the development and progression of hepatocellular carcinoma (HCC). Similarly, hepatoblastoma, the most common childhood liver cancer, is frequently associated with β-catenin mutations, which activate Wnt/β-catenin signaling. HCCs with activation of the Wnt/β-catenin pathway have unique gene expression patterns and pathological and clinical features. Accordingly, they are highly differentiated with retaining hepatocyte-like characteristics and tumorigenic. Activation of the Wnt/β-catenin pathway in HCC also alters the state of immune cells, causing "immune evasion" with inducing resistance to immune checkpoint inhibitors, which have recently become widely used to treat HCC. Activated Wnt/β-catenin signaling exhibits these phenomena in liver tumorigenesis through the expression of downstream target genes, and the molecular basis is still poorly understood. In this review, we describe the physiological roles of Wnt/b-catenin signaling and then discuss their characteristic changes by the abnormal activation of Wnt/b-catenin signaling. Clarification of the mechanism would contribute to the development of therapeutic agents in the future.

en: In Vitro Cellular & Developmental Biology. Animal


en: 【核酸医薬が飛躍する時】肝がんに対する核酸医薬品の開発動向

ja: 【核酸医薬が飛躍する時】肝がんに対する核酸医薬品の開発動向

en: 肝がんは世界的に死亡率の高い難治性のがんであり,進行がんに対する既存の治療法は有効性が限定的である．アンチセンスやsiRNAなどの核酸医薬は,肝がんの発生や進行に関与する多様なシグナル経路を標的とすることができるため,有望なモダリティとして注目されている．核酸修飾技術や薬物送達技術の進歩により,いくつかの核酸医薬は前臨床研究や臨床試験で抗腫瘍効果や安全性が示されている．今後,さらなる研究開発によって,核酸医薬が肝がんの治療薬として治療成績の向上に貢献することが期待される．(著者抄録)

en: Medical Science Digest

ja: Medical Science Digest


en: Dickkopf signaling, beyond Wnt-mediated biology.

en: Dickkopf1 (DKK1) was originally identified as a secreted protein that antagonizes Wnt signaling. Although DKK1 is essential for the developmental process, its functions in postnatal and adult life are unclear. However, evidence is accumulating that DKK1 is involved in tumorigenesis in a manner unrelated to Wnt signaling. In addition, recent studies have revealed that DKK1 may control immune reactions, although the relationship of this to Wnt signaling is unknown. Other DKK family members, DKK2-4, are likely to have their own functions. Here, we review the possible novel functions of DKKs. We summarize the characteristics of receptors of DKKs and the signaling mechanisms through DKKs and their receptors, provide evidence showing that DKKs are involved in tumor aggressiveness independently of Wnt signaling, and emphasize promising cancer therapies targeting DKKs and receptors. Lastly, we discuss various physiological and pathological processes controlled by DKKs.

en: Seminars in Cell & Developmental Biology


en: Epithelial morphogenesis and implication in tumorigenesis due to its abnormality

ja: 上皮管腔形態形成の分子機構とその異常による腫瘍形成

en: Seikagaku

ja: 生化学


en: GREB1, a novel therapeutic target of Wnt signaling, promotes the development of hepatoblastoma by suppressing TGFβ signaling

ja: 肝芽腫におけるWntシグナル関連新規創薬標的GREB1の同定と核酸医薬の開発

en: J Jpn Soc Pediatr Hematol Oncol

ja: 日本小児血液・がん学会雑誌


en: Wnt signaling pathways in cancers: key targets and implications in cancer therapy

ja: Wntシグナルの研究を基盤とした新規の抗がん剤の開発

en: Leading Author's

ja: 領域融合レビュー


en: Arl4c is a key regulator of tubulogenesis and tumourigenesis as a target gene of Wnt-β-catenin and growth factor-Ras signalling.

en: Epithelial tubular morphogenesis (tubulogenesis) is a fundamental morphogenetic process of many epithelial organs. In this developmental process, epithelial cells migrate, proliferate, polarize and differentiate towards surrounding mesenchymal tissue to form tubule structures. Although epithelial tissue structures are basically stable in the postnatal period, epithelial cells regain highly proliferative and invasive potentials within mesenchymal tissue during tumour formation (tumourigenesis). Therefore, there must be a common molecular basis orchestrating the cellular behaviours involved in both tubulogenesis and tumourigenesis. ADP-ribosylation factor (Arf)-like protein 4c (Arl4c), which belongs to the small GTP-binding protein family, is expressed by the simultaneous activation of Wnt-β-catenin and growth factor-Ras-mitogen-activated protein kinase signalling, was identified as an essential regulator of tubulogenesis. Arl4c expression was also involved in the tumour formation of colorectal and lung cancers. In this review, we focus on Arl4c as a novel Wnt signal target molecule that links epithelial tubulogenesis to tumourigenesis.

en: The Journal of Biochemistry

ja: The Journal of Biochemistry


en: 【消化管の再生医療】In vitro実験系を用いた上皮管腔組織形成の分子基盤の確立

en: 生体を構成する呼吸器系，尿路系，外分泌系などの器官は，極性化した上皮細胞から成る管(チューブ)状の上皮管腔組織が基本構成単位となる．上皮管腔組織の形成・維持にはWntをはじめ上皮成長因子(EGF)や線維芽細胞増殖因子(FGF)，骨形成因子(BMP)といった液性因子や，基底膜などの細胞外基質(ECM)からの接着シグナルが必要不可欠である．組織幹細胞の研究が急速に進展している一方で，上皮細胞集団からなる組織・器官の形成と維持の分子・細胞レベルでの理解は大きく立ち遅れている．最近，培養上皮細胞やマウス胎児器官を用いて，WntがEGFなどの増殖因子と協調的に上皮細胞集団の細胞骨格や形態，増殖を制御し，管腔組織形成を誘導する新たな機構が明らかになってきた．これらの上皮管腔組織形成の分子基盤の解明は，消化管形成機構の理解と再生医療への応用に貢献すると期待される．(著者抄録)


en: Role of Wnt 5a signaling in the regulation of cell polarity, migration, and adhesion

ja: 特集 細胞接着の制御 Wnt 5aシグナルによる細胞の極性と遊走·接着の制御

en: 生体の科学

ja: 生体の科学


en: 特集 Wnt協奏曲:新たな活性化機構と他の増殖·分化シグナルとの協調による形態形成 (第2部)Wntシグナルと幹細胞からの組織形態形成 Wntと増殖因子の協調的シグナルによる上皮管腔組織形成

en: 細胞工学

ja: 細胞工学


en: 【シグナル伝達研究最前線2012 翻訳後修飾，解析技術，疾患との連関から創薬応用まで】(第3章)シグナル伝達の破綻と疾患との連関 Wntシグナルの異常と消化器がん

en: ショウジョウバエの遺伝学に端を発したWnt研究は，腫瘍医学や発生生物学においても解析が進み，多様な研究領域に展開した．特に腫瘍医学領域では，大腸がんにおけるWntシグナル研究は組織幹細胞マーカーLgr5の発見に貢献した．また，がんの発症，悪性化には慢性炎症の存在が背景となることが示唆され，炎症とWntシグナルとの関連も新たな研究領域になりつつある．さらに，Wntシグナル経路の活性を調節することによるがんの治療戦略も考案されてきている．(著者抄録)

en: 実験医学

ja: 実験医学


en: 【秒進分歩する癌研究と分子標的治療 発癌から浸潤・転移に至るメカニズム解明とトランスレーショナルリサーチの最前線】基礎研究編:発癌から浸潤・転移に至るメカニズム解明 発癌シグナルの原因究明 Wntシグナルネットワークの異常と癌

en: ショウジョウバエの遺伝学に端を発したWnt研究は，腫瘍医学や発生生物学においても解析が進み，多様な研究領域に展開した．Wntは生物種を越えて保存されており，動物の発生に必須な分泌タンパク質である．Wntは細胞膜受容体に結合することにより，多彩な細胞内シグナル経路を活性化し，細胞の増殖や分化，運動，極性を制御する．したがって，Wntシグナル経路の異常が種々の疾患の原因となりうる．特に，Wntシグナル経路の構成タンパク質の遺伝子異常や発現異常がヒト癌の発症や悪性化に関与することが明らかになってきている．また，Wntシグナル経路の活性を調節することによる癌の治療戦略も考案されてきている．(著者抄録)


en: New insights into the mechanism of Wnt signaling pathway activation.

en: Wnts compromise a large family of secreted, hydrophobic glycoproteins that control a variety of developmental and adult processes in all metazoan organisms. Recent advances in the Wnt-signal studies have revealed that distinct Wnts activate multiple intracellular cascades that regulate cellular proliferation, differentiation, migration, and polarity. Although the mechanism by which Wnts regulate different pathways selectively remains to be clarified, evidence has accumulated that in addition to the formation of ligand-receptor pairs, phosphorylation of receptors, receptor-mediated endocytosis, acidification, and the presence of cofactors, such as heparan sulfate proteoglycans, are also involved in the activation of specific Wnt pathways. Here, we review the mechanism of activation in Wnt signaling initiated on the cell-surface membrane. In addition, the mechanisms for fine-tuning by cross talk between Wnt and other signaling are also discussed.

en: International Review of Cell and Molecular Biology


en: β-catenin-independent Wnt signaling regulates cell migration, polarity, and morphogenesis

ja: β-カテニン非依存性 Wnt シグナルによる細胞運動・極性および形態形成制御

en: TCRC

ja: 組織培養研究