Regulation of Features of Liver Cancer Stem-like Cells through the TCF-4/CLAUDIN-2/HES1 Axis

• Project/Area Number: 17K09445
• 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): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: T-cell factor-4 / Wnt / Claudin-2 / Hes1 / TCF-4 / 肝細胞癌 / CLAUDIN-2 / HES1 / Sphere / Wntシグナル

Outline of Final Research Achievements

We investigated the Wnt-Notch crosstalk in liver cancer cells. Loss of SxxSS motif in TCF-4 led to upregulation of CLAUDIN-2 (CLDN2) mRNA. This finding coupled with upregulation of HES1 was also reproduced at protein levels in both sphere-forming J cells, that do not have SxxSS, and K-mutant cells, having engineered SxxSA motif. These findings suggested HES1 expression was regulated by the critical transcription factor TCF-4 isoforms in liver cancer cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では，独自のTCF-4 isoformを用いWnt-Notch crosstalkの解明にアプローチする点が最大の特色であった．Cancer sphereに濃縮されるCLAUDIN-2はleaky tight junctionを形成し，かつNotchシグナル活性化を促進しHES1発現を増強することで癌幹細胞のstemness維持に寄与していると考えている．意義としては，Wnt/TCF-4下流分子CLAUDIN-2からのNotchシグナルリレーが明らかになり，CSCに対する新規治療標的を探索できる可能性を増やすことができる点だと考えている．

Research Products

• [Presentation] Two-faced effects of Claudin-2 on Wnt signaling in liver cancer cells (2019)
  • Author(s): Hironori Koga, Hideki Iwamoto, Takahiko Sakaue, Takuji Torimura
  • Organizer: 第78回 日本癌学会学術総会
• [Presentation] Involvement of Wnt Signaling in Two-faced Actions of Claudin-2 in Liver Cancer Cells (2019)
  • Author(s): Hironori Koga, Yasuko Imamura, Toru Nakamura, Hideki Iwamoto, Takahiko Sakaue, Atsutaka Masuda, Toshimitsu Tanaka, Dan Nakano, Hiroyuki Suzuki, Hirohisa Yano, Takuji Torimura
  • Organizer: AASLD 2019 “The Liver Meeting”
• [Presentation] The Wnt target CLAUDIN-2 regulates tumorigenesis and stemness in human liver cancer cells (2018)
  • Author(s): Hironori Koga, Fumitaka Wada, Mitsuhiko Abe, Hideki Iwamoto, Toru Nakamura, Takahiko Sakaue, Atsutaka Masuda, Toshimitsu Tanaka, Hirohisa Yano and Takuji Torimura
  • Organizer: The 109th Annual Meeting of the American Association for Cancer Research (AACR)
  • Int'l Joint Research
• [Presentation] Claudin-2 activates LKB1-AMPK signals, thereby inducing cellcycle arrest and autophagy in liver cancer cells (2018)
  • Author(s): Hironori Koga, Fumitaka Wada, Takahiko Sakaue, Hideki Iwamoto,Mitsuhiko Abe, Takuji Torimura
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Claudin-2 Activates LKB1-AMPK Signals, Thereby Inducing Cell-Cycle Arrest and Autophagy in Liver Cancer Cells (2018)
  • Author(s): Hironori Koga, Yasuko Imamura, Fumitaka Wada, Mitsuhiko Abe, Hideki Iwamoto, Toru Nakamura, Takahiko Sakaue, Atsutaka Masuda, Toshimitsu Tanaka, Hirohisa Yano, Takuji Torimura
  • Organizer: The 69th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] HES1 critically regulates sphere-forming ability and tumorigenesis in WNT signal-engineered liver cancer cells (2017)
  • Author(s): Hironori Koga, Toru Nakamura, Fumitaka Wada, Hideki Iwamoto, Atsutaka Masuda, Takahiko Sakaue, Toshimitsu Tanaka, Mitsuhiko Abe, Jun Akiba, Hirohisa Yano, Takuji Torimura
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] The Wnt Target Gene CLAUDIN-2 Regulates Tumorigenesis of Combined Hepatocellular-Cholangiocarcinoma Cells (2017)
  • Author(s): Hironori Koga, Yasuko Imamura, Fumitaka Wada, Yu Ikezono, Mitsuhiko Abe, Hideki Iwamoto, Toru Nakamura, Takahiko Sakaue, Atsutaka Masuda, Toshimitsu Tanaka, Hirohisa Yano, Takuji Torimura
  • Organizer: The Liver Meeting 2017
  • Int'l Joint Research
• [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] 久留米大学医学部内科学講座消化器内科部門
  • URL: http://www.kurume-shoukaki.jp/
• [Remarks] 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/
• [Remarks] すこやかな『次代』と『人』を創る研究拠点大学へ: 先端がん治療・研究による挑戦
  • URL: https://www.kurume-u.ac.jp/site/branding/
• [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/
• [Remarks] 「すこやかな『次代』と『人』を創る研究拠点大学へ～先端がん治療・研究による挑戦～」
  • URL: https://www.kurume-u.ac.jp/site/branding/