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Molecular switch for WNT5A/B expression through TCF-4 isoforms in human liver cancer cells

Research Project

Project/Area Number 26461025
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionKurume University

Principal Investigator

Koga Hironori  久留米大学, 医学部, 教授 (90268855)

Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
KeywordsWntシグナル / T-cell factor-4 / 癌幹細胞 / TCF-4 / Wnt / isoform / Hes1 / Notch
Outline of Final Research Achievements

We have demonstrated that a mutant isoform (269A) of the SxxSS-harboring TCF-4K robustly expressed WNT5A at both mRNA and protein levels in human liver cancer cells. ChIP assay revealed that the mutant TCF-4 could directly bind to promoter region of WNT5A gene, suggesting the motif contributed to regulate the gene expression. Knockdown of WNT5A resulted in upregulation of the EMT regulator SLUG. These findings suggest that TCF-4 regulates WNT5A expression in a SxxSS motif-dependent manner, thereby contributing to phenotypic changes, including EMT. I addition, HIPK-2 was suggested to be responsible for phosphorylation of serine residues of SxxSS.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (26 results)

All 2017 2016 2015 2014 Other

All Journal Article (12 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 12 results,  Acknowledgement Compliant: 3 results,  Open Access: 8 results) Presentation (12 results) (of which Int'l Joint Research: 4 results) Remarks (2 results)

  • [Journal Article] Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1.2017

    • Author(s)
      Ikezono Y, Koga H, Akiba J, Abe M, Yoshida T, Wada F, Nakamura T, Iwamoto H, Masuda A, Sakaue T, Yano H, Tsuruta O, Torimura T.
    • Journal Title

      Molecular Cancer Research

      Volume: -

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice.2016

    • Author(s)
      Kawaguchi T, Ueno T, Nogata Y, Hayakawa M, Koga H, Torimura T
    • Journal Title

      International Journal of Molecular Medicine

      Volume: 39 Issue: 2 Pages: 407-414

    • DOI

      10.3892/ijmm.2016.2831

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pancreatic DCLK1 marks quiescent but oncogenic progenitors: a possible link to neuroendocrine tumors.2016

    • Author(s)
      Koga H, Ikezono Y, Torimura T.
    • Journal Title

      Stem Cell Investigation

      Volume: 3 Pages: 37-37

    • DOI

      10.21037/sci.2016.08.03

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Alternative treatments in advanced hepatocellular carcinoma patients with progressive disease after sorafenib treatment: a prospective multicenter cohort study.2016

    • Author(s)
      Nakano M, Tanaka M, Kuromatsu R, Nagamatsu H, Satani M, Niizeki T, Okamura S, Iwamoto H, Shimose S, Shirono T, Noda Y, Koga H, Torimura T; Kurume Liver Cancer Study Group Of Japan.
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 39 Pages: 64400-64409

    • DOI

      10.18632/oncotarget.10794

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ex vivo expansion of circulating CD34+ cells enhances the regenerative effect on rat liver cirrhosis2016

    • Author(s)
      Toru Nakamura, Hironori Koga, Hideki Iwamoto, Victor Tsutsumi, Yasuko Imamura, Masako Naitou, Atsutaka Masuda, Yu Ikezono, Mitsuhiko Abe, Fumitaka Wada, Takahiko Sakaue, Takato Ueno, Masaaki Ii, Cantas Alev, Atsuhiko Kawamoto, Takayuki Asahara, Takuji Torimura
    • Journal Title

      Molecular Therapy - Methods & Clinical Development

      Volume: 3 Pages: 1-13

    • DOI

      10.1038/mtm.2016.25

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Antiangiogenic and Antitumor Activities of Aflibercept, a Soluble VEGF Receptor-1 and -2, in a Mouse Model of Hepatocellular Carcinoma.2016

    • Author(s)
      Torimura T, Iwamoto H, Nakamura T, Abe M, Ikezono Y, Wada F, Sakaue T, Masuda H, Hashimoto O, Koga H, Ueno T, Yano H.
    • Journal Title

      Neoplasia

      Volume: 18 Issue: 7 Pages: 413-424

    • DOI

      10.1016/j.neo.2016.05.001

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatic arterial infusion chemoembolization therapy for advanced hepatocellular carcinoma: multicenter phase II study.2016

    • Author(s)
      Nagamatsu H, Sumie S, Niizeki T, Tajiri N, Iwamoto H, Aino H, Nakano M, Shimose S, Satani M, Okamura S, Kuromatsu R, Matsugaki S, Kurogi J, Kajiwara M, Koga H, Torimura T.
    • Journal Title

      Cancer Chemotherapy and Pharmacology

      Volume: 77 Issue: 2 Pages: 243-250

    • DOI

      10.1007/s00280-015-2892-7

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] High expression of the putative cancer stem cell marker, DCLK1, in rectal neuroendocrine tumors.2015

    • Author(s)
      Ikezono YU, Koga H, Abe M, Akiba J, Kawahara A, Yoshida T, Nakamura T, Iwamoto H, Yano H, Kage M, Sata M, Tsuruta O, Torimura T.
    • Journal Title

      Oncology Letters

      Volume: 10 Issue: 4 Pages: 2015-2020

    • DOI

      10.3892/ol.2015.3513

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study.2015

    • Author(s)
      Nakano M, Tanaka M, Kuromatsu R, Nagamatsu H, Tajiri N, Satani M, Niizeki T, Aino H, Okamura S, Iwamoto H, Shimose S, Shirono T, Koga H, Torimura T; Kurume Liver Cancer Study Group of Japan.
    • Journal Title

      Cancer Medicine

      Volume: 12 Issue: 12 Pages: 1836-1843

    • DOI

      10.1002/cam4.548

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of fucoidan on proliferation, AMP-activated protein kinase, and downstream metabolism- and cell cycle-associated molecules in poorly differentiated human hepatoma HLF cells.2015

    • Author(s)
      Kawaguchi T, Hayakawa M, Koga H, Torimura T.
    • Journal Title

      International Journal of Oncology

      Volume: 46 Issue: 5 Pages: 2216-2222

    • DOI

      10.3892/ijo.2015.2928

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of hypoxia-inducible factor via upregulation of von Hippel-Lindau protein induces "angiogenic switch off" in a hepatoma mouse model.2015

    • Author(s)
      Iwamoto H, Nakamura T, Koga H, Izaguirre-Carbonell J, Kamisuki S, Sugawara F, Abe M, Iwabata K, Ikezono Y, Sakaue T, Masuda A, Yano H, Ohta K, Nakano M, Shimose S, Shirono T, Torimura T.
    • Journal Title

      Molecular Therapy Oncolytics

      Volume: 2 Pages: 15020-15020

    • DOI

      10.1038/mto.2015.20

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD34+ cell therapy is safe and effective in slowing the decline of hepatic reserve function in patients with decompensated liver cirrhosis2014

    • Author(s)
      Nakamura T, Torimura T, Iwamoto H, Kurogi J, Inoue H, Hori Y, Sumie S, Fukushima N, Sakata M, Koga H, et al.
    • Journal Title

      J Gastroenterol Hepatol

      Volume: (in press) Issue: 10 Pages: 1830-1838

    • DOI

      10.1111/jgh.12622

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Presentation] Wnt下流分子Claudin-2による 肝癌Notchシグナルの制御2016

    • Author(s)
      古賀浩徳,矢野博久,鳥村拓司
    • Organizer
      第29回 日本バイオセラピィ学会学術集会総会
    • Place of Presentation
      久留米
    • Year and Date
      2016-12-01
    • Related Report
      2016 Annual Research Report
  • [Presentation] TCF-4 isoform upregulates CLAUDIN-2, thereby activating NOTCH signaling in human liver cancer cells2016

    • Author(s)
      Koga H, Wada F, Akiba J, Ikezono Y, Iwamoto H, Nakamura T, Masuda A, Sakaue T, Yano H, Torimura T.
    • Organizer
      第75回 日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] 幹細胞未分化状態維持因子Hes1はNotchおよびWntからのdual regulationを受ける2016

    • Author(s)
      古賀浩徳,矢野博久,鳥村拓司
    • Organizer
      第102回 日本消化器病学会総会
    • Place of Presentation
      東京
    • Year and Date
      2016-04-21
    • Related Report
      2016 Annual Research Report
  • [Presentation] Regulation of Hes1 expression by the Wnt transcription factor T-cell factor-42016

    • Author(s)
      Koga H, Imamura Y, Ikezono Y, Wada F, Nakamura T, Iwamoto H, Masuda A, Sakaue T, Yano H, Torimura T.
    • Organizer
      AACR Annual Meeting 2016
    • Place of Presentation
      ニューオーリンズ
    • Year and Date
      2016-04-16
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] T-cell Factor-4 isoforms participate in EMT through Wnt5a induction in human liver cancer cells2015

    • Author(s)
      Koga H, Nakamura T, Abe M, Ikezono Yu, Wada F, Iwamoto H, Sakaue T, Yano H, Torimura T
    • Organizer
      UEGW 2015
    • Place of Presentation
      バルセロナ
    • Year and Date
      2015-10-24
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Expression of HES1, a Notch regulator of biliary features, is regulated by T-cell factor-4 isoforms2015

    • Author(s)
      Koga H, Yano H, Torimura T
    • Organizer
      JDDW 2015
    • Place of Presentation
      東京都(品川)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Research-status Report
  • [Presentation] The SxxSS motif of T-cell Factor-4 isoforms regulatesWnt5a expression and EMT in human liver cancer cells2015

    • Author(s)
      Koga H, Nakamura T, Abe M, Ikezono Yu, Wada F, Iwamoto H, Sakaue T, Yano H, Torimura T
    • Organizer
      APPLE 2015
    • Place of Presentation
      大阪市
    • Year and Date
      2015-07-03
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] TCF-4の構造的差異による肝癌細胞stemness形質の制御2015

    • Author(s)
      古賀浩徳、Jack R. Wands、鳥村拓司
    • Organizer
      第51回日本肝臓学会総会
    • Place of Presentation
      熊本市
    • Year and Date
      2015-05-21
    • Related Report
      2015 Research-status Report
  • [Presentation] The SxxSS motif of T-cell Factor-4 isoforms regulates Wnt5a expression and EMT in human liver cancer cells2015

    • Author(s)
      Koga H, Nakamura T, Abe M, Ikezono Y, Wada F, Yano H, Torimura T.
    • Organizer
      AACR Annual Meeting 2015
    • Place of Presentation
      フィラデルフィア
    • Year and Date
      2015-04-18
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Wntシグナル転写因子TCF-4 isoformによる細胞機能調節機構2014

    • Author(s)
      古賀浩徳、中村徹、安倍満彦、池園友、和田史孝、矢野博久、鳥村拓司
    • Organizer
      第46回 日本臨床分子形態学会総会・学術集会(シンポジウム2)
    • Place of Presentation
      TKP市ヶ谷カンファレンスセンター,東京
    • Year and Date
      2014-10-17
    • Related Report
      2014 Research-status Report
  • [Presentation] The SxxSS motif of TCF-4 isoforms regulates non-canonical Wnt signaling in liver cancer cells2014

    • Author(s)
      Hironori Koga, Miran Kim, Toru Nakamura, Mitsuhiko Abe, Yu Ikezono, Fumitaka Wada, Osamu Hashimoto, Hirohisa Yano, Jack R. Wands, Takuji Torimura
    • Organizer
      第73回 日本癌学会学術総会
    • Place of Presentation
      パシフィコ横浜,神奈川県横浜市
    • Year and Date
      2014-09-27
    • Related Report
      2014 Research-status Report
  • [Presentation] The Wnt signal transcription factor TCF-4 directly regulates Bcl-xL expression in human hepatocellular carcinoma cells2014

    • Author(s)
      Hironori Koga, Miran Kim, Anna Nakamura, Hirohisa Yano, Mitsuhiko Abe, Yu Ikezono, Toru Nakamura, Takuji Torimura, Jack R. Wands, and Michio Sata
    • Organizer
      AACR 2014
    • Place of Presentation
      San Diego Convention Center, San Diego, CA, USA
    • Year and Date
      2014-04-06
    • Related Report
      2014 Research-status Report
  • [Remarks] 久留米大学先端癌治療研究センター

    • URL

      http://www.med.kurume-u.ac.jp/med/sentanca/

    • Related Report
      2016 Annual Research Report 2015 Research-status Report
  • [Remarks] 久留米大学先端癌治療研究センター肝癌部門

    • URL

      http://www.med.kurume-u.ac.jp/med/sentanca/kangan/

    • Related Report
      2014 Research-status Report

URL: 

Published: 2014-04-04   Modified: 2018-03-22  

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