Analysis of a novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion

• Project/Area Number: 26461031
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Ikenoue Tsuneo 東京大学, 医科学研究所, 准教授 (80396712)
• Co-Investigator(Kenkyū-buntansha): 古川 洋一 東京大学, 医科学研究所, 教授 (20272560) ; 伊地知 秀明 東京大学, 医学部附属病院, 講師 (70463841)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝内胆管癌 / マウスモデル / 起源細胞 / Kras / Pten / Notchシグナル

Outline of Final Research Achievements

We have established a novel mouse model of ICC by liver-specific Kras activation and Pten deletion. An activating mutation of Kras in combination with deletion of Pten was introduced in embryonic hepatic bipotential progenitor cells and mature hepatocytes using the Cre-loxP system. As a result, liver-specific Kras activation and homozygous Pten deletion cooperated to induce ICCs exclusively. In contrast, Kras activation in combination with heterozygous Pten deletion induced both ICCs and HCCs, whereas Kras activation alone resulted in HCCs but not ICCs. Furthermore, a cell-lineage visualization system using tamoxifen-inducible Cre-loxP demonstrated that the ICCs did not originate from hepatocytes but from cholangiocytes. Our data suggest that mice carrying liver-specific Kras activation in combination with homozygous Pten deletion should be useful for the investigation of therapeutic strategies for human ICC.

Research Products

• [Journal Article] A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion. (2016)
  • Author(s): Ikenoue T, Terakado Y, Nakagawa H, Hikiba Y, Fujii T, Matsubara D, Noguchi R, Zhu C, Yamamoto K, Kudo Y, Asaoka Y, Yamaguchi K, Ijichi H, Tateishi K, Fukushima N, Maeda S, Koike K, Furukawa Y
  • Journal Title: Sci Rep Volume: 印刷中 Issue: 1 Pages: 23899-23899
  • DOI: 10.1038/srep23899
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A potent therapeutics for gallbladder cancer by combinatorial inhibition of the MAPK and mTOR signaling networks. (2016)
  • Author(s): Mohri D, Ijichi H, Miyabayashi K, Takahashi R, Kudo Y, Sasaki T, Asaoka Y, Tanaka Y, Ikenoue T, Tateishi K, Tada M, Isayama H, Koike K.
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 7 Pages: 711-21
  • DOI: 10.1007/s00535-015-1145-1
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of a New Small Bowel Adenocarcinoma Cell Line and Screening of Anti-Cancer Drug against Small Bowel Adenocarcinoma (2015)
  • Author(s): Hirobumi Suzuki, Yoshihiro Hirata, Nobumi Suzuki, Sozaburo Ihara, Kosuke Sakitani, Yuka Kobayashi, Hiroto Kinoshita,Yoku Hayakawa, Atsuo Yamada, Hirotsugu Watabe, Keisuke Tateishi, Tsuneo Ikenoue, Yutaka Yamaji, and Kazuhiko Koike
  • Journal Title: American Journal of Pathology Volume: 185 Issue: 2 Pages: 550-562
  • DOI: 10.1016/j.ajpath.2014.10.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. (2014)
  • Author(s): Yamamoto K, Tateishi K, Kudo Y, Sato T, Yamamoto S, Miyabayashi K, Asaoka Y, Ijichi H, Hirata Y, Otsuka M, Nakai Y, Isayama H, Ikenoue T, Kurokawa M, Fukayama M, Kokudo N, Omata M and Koike K.
  • Journal Title: Carcinogenesis Volume: 35 Issue: 11 Pages: 2404-14
  • DOI: 10.1093/carcin/bgu136
  • Peer Reviewed / Open Access
• [Presentation] Analysis of the cellular origin of intrahepatic cholangiocarcinoma using a novel mouse model (2016)
  • Author(s): Yumi Terakado, Tsuneo Ikenoue, Rei Noguchi, Chi Zhu, Daisuke Matsubara, Kiyoshi Yamaguchi, Yoichi Furukawa
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
  • Int'l Joint Research
• [Presentation] Molecular characterization of an intrahepatic cholangiocarcinoma mouse model induced by Kras mutation and Pten deletion (2016)
  • Author(s): Tsuneo Ikenoue, Yumi Terakado, Kiyoshi Yamaguchi, Yoichi Furukawa
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Analysis of the role of Notch-Rbpj axis in intrahepatic cholangiocarcinoma (2016)
  • Author(s): Yumi Terakado, Tsuneo Ikenoue, Kiyoshi Yamaguchi, Yoichi Furukawa
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Analysis of the role of Notch-Rbpj axis in intrahepatic cholangiocarcinoma (2015)
  • Author(s): Terakado Y, Ikenoue T, Yamaguchi K, Asaoka Y, , Ijichi H, Tateishi K, Koike K, Furukawa Y.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2015-10-08
  • Int'l Joint Research
• [Presentation] Molecular characterization of an intrahepatic cholangiocarcinoma mouse model induced by Kras mutation and Pten deletion. (2015)
  • Author(s): Ikenoue T, Terakado Y, Yamaguchi K, Asaoka Y, , Ijichi H, Tateishi K, Koike K, Furukawa Y.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2015-10-08
  • Int'l Joint Research
• [Presentation] 肝特異的Kras活性化及びPten欠失による新規肝内胆管癌マウスモデルの樹立と解析 (2014)
  • Author(s): 寺門侑美、池上恒雄、山口貴世志、浅岡良成、伊地知秀明、立石敬介、小池和彦、古川洋一
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-26
• [Presentation] 次世代シークエンサーを用いての日本人胆道がんの包括的遺伝子解析 (2014)
  • Author(s): 野口玲, 山口貴世志, 荒川 茉莉子, 大田泰徳, 池上恒雄, 古川洋一
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-26