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

• Project/Area Number: 26461025
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kurume 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: ¥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)
• Keywords: Wnt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.

Research Products

• [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: -
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Ex vivo expansion of circulating CD34+ cells enhances the regenerative effect on rat liver cirrhosis (2016)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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 cirrhosis (2014)
  • 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
  • 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
• [Presentation] TCF-4 isoform upregulates CLAUDIN-2, thereby activating NOTCH signaling in human liver cancer cells (2016)
  • 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
• [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
• [Presentation] Regulation of Hes1 expression by the Wnt transcription factor T-cell factor-4 (2016)
  • 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
  • Int'l Joint Research
• [Presentation] T-cell Factor-4 isoforms participate in EMT through Wnt5a induction in human liver cancer cells (2015)
  • 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
  • Int'l Joint Research
• [Presentation] Expression of HES1, a Notch regulator of biliary features, is regulated by T-cell factor-4 isoforms (2015)
  • 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
• [Presentation] The SxxSS motif of T-cell Factor-4 isoforms regulatesWnt5a expression and EMT in human liver cancer cells (2015)
  • 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
  • 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
• [Presentation] The SxxSS motif of T-cell Factor-4 isoforms regulates Wnt5a expression and EMT in human liver cancer cells (2015)
  • 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
  • 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
• [Presentation] The SxxSS motif of TCF-4 isoforms regulates non-canonical Wnt signaling in liver cancer cells (2014)
  • 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
• [Presentation] The Wnt signal transcription factor TCF-4 directly regulates Bcl-xL expression in human hepatocellular carcinoma cells (2014)
  • 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
• [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/
• [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/