Establishment of new mouse models for investigating the effect of fatty liver on intrahepatic bile duct cancer development

• Project/Area Number: 18K07968
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Gifu University
• Principal Investigator: Shirakami Yohei 岐阜大学, 医学部附属病院, 助教 (50632816)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 肝内胆管癌 / 脂肪肝 / 肥満 / レチノイド

Outline of Final Research Achievements

This study was conducted to establish a novel animal model for intrahepatic cholangiocarcinoma. The liver of obese db/db mice administered the colorectal carcinogen azoxymethane exhibited obesity-induced fatty liver, proliferative changes and dysplasia of the small bile ducts, as well as cholangiocarcinoma. Gene expressions related to inflammatory cytokines and IGF signaling pathway were elevated in the liver of db/db mice with bile duct lesions, suggesting that chronic inflammation caused by the development of hepatic steatosis promoted proliferative changes in bile ducts and intrahepatic cholangiocarcinoma.

Academic Significance and Societal Importance of the Research Achievements

生活習慣の変化から肥満人口が増加しているが、肥満の存在によりさまざまながんの発生率が上昇することが知られている。本研究結果は、肥満に伴う肝脂肪化の進展による慢性炎症が、肝内胆管癌の発生に関与することを示唆するとともに、肥満を呈するマウスを用いた肝内胆管癌モデルがヒト胆管癌の病態を反映した新規動物モデルとして有用であり、発癌および進展機序の解明や治療法の開発に寄与する可能性を示している。

Research Products

• [Journal Article] Novel FXR agonist nelumal A suppresses colitis and inflammation-related colorectal carcinogenesis (2021)
  • Author(s): Miyazaki Tsuneyuki、Shirakami Yohei、Mizutani Taku、Maruta Akinori、Ideta Takayasu、Kubota Masaya、Sakai Hiroyasu、Ibuka Takashi、Genovese Salvatore、Fiorito Serena、Taddeo Vito Alessandro、Epifano Francesco、Tanaka Takuji、Shimizu Masahito
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 492-492
  • DOI: 10.1038/s41598-020-79916-5
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas (2021)
  • Author(s): Tomita Hiroyuki、Tanaka Kaori、Hirata Akihiro、Okada Hideshi、Imai Hisashi、Shirakami Yohei、Ohnishi Kotaro、Sugie Shigeyuki、Aoki Hitomi、Hatano Yuichiro、Noguchi Kei、Kanayama Tomohiro、Niwa Ayumi、Suzui Natsuko、Miyazaki Tatsuhiko、Tanaka Takuji、Akiyama Haruhiko、Shimizu Masahito、Yoshida Kazuhiro、Hara Akira
  • Journal Title: Cell Reports Volume: 34 Issue: 8 Pages: 108772-108772
  • DOI: 10.1016/j.celrep.2021.108772
  • Peer Reviewed / Open Access
• [Journal Article] Alpha-Glucosidase Inhibitor Voglibose Suppresses Azoxymethane-Induced Colonic Preneoplastic Lesions in Diabetic and Obese Mice. (2020)
  • Author(s): Kato J, Shirakami Y, Mizutani T, Kubota M, Sakai H, Ibuka T, Shimizu M.
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 6 Pages: 2226-2226
  • DOI: 10.3390/ijms21062226
  • Peer Reviewed / Open Access
• [Journal Article] Suppressive effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin on colorectal tumorigenesis in diabetic and obese mice. (2019)
  • Author(s): Kato J, Shirakami Y, Ohnishi M, Mizutani T, Kubota M, Sakai H, Ibuka T, Tanaka T, Shimizu M.
  • Journal Title: Oncol Rep. Volume: 42 Pages: 2797-2805
  • DOI: 10.3892/or.2019.7357
  • Peer Reviewed / Open Access
• [Journal Article] Acute cytomegalovirus infection in an immunocompetent patient with ulcerative colitis: A case report. (2019)
  • Author(s): Maeda T, Sakai H, Ozawa N, Sugiyama T, Takada J, Kubota M, Ibuka T, Shirakami Y, Araki H, Shimizu M.
  • Journal Title: Exp Ther Med. Volume: 18 Pages: 2271-2277
  • DOI: 10.3892/etm.2019.7823
  • Peer Reviewed / Open Access
• [Journal Article] Meeting report of the 14th Japan Korea joint symposium on cancer and aging research: current status of translational research and approaches to precision medicine (2019)
  • Author(s): Sueoka Eisaburo、Watanabe Tatsuro、Mashima Tetsuo、Shirakami Yohei、Komori Atsumasa、Matsuo Keitaro、Yoshikawa Hiroshi Y.、Cho Kyung A、Park Tae Jun、Seimiya Hiroyuki、Kim Eung-Gook、Suganuma Masami、Chung Junho
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 印刷中 Issue: 5 Pages: 1263-1271
  • DOI: 10.1007/s00432-019-02887-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diabetes Mellitus and Colon Carcinogenesis: Expectation for Inhibition of Colon Carcinogenesis by Oral Hypoglycemic Drugs. (2019)
  • Author(s): Kato J, Shirakami Y, Shimizu M.
  • Journal Title: Gastrointest Disord. Volume: 1 Issue: 2 Pages: 273-289
  • DOI: 10.3390/gidisord1020023
  • Peer Reviewed / Open Access
• [Presentation] Effects of fatty liver on development of intrahepatic cholangiocarcinoma (2018)
  • Author(s): 白上洋平、加藤潤一、水谷 拓、河内隆宏、境 浩康、富田弘之、田中卓二、清水雅仁
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 核内受容体とそのリガンドの医学 (2018)
  • Author(s): 白上洋平、境 浩康、清水雅仁
  • Organizer: 第29回日本レチノイド研究会学術集会
• [Presentation] Non-alcoholic steatohepatitis-related hepatocarcinogenesis is suppressed in mice lacking hepatic retinoid storage (2018)
  • Author(s): Yohei Shirakami, Takayasu Ideta, Hiroyasu Sakai, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima
  • Organizer: Asian Pacific Association for the Study of the Liver Single Topic Conference
  • Int'l Joint Research
• [Presentation] Antidiabetic agents for cancer prevention (2018)
  • Author(s): Yohei Shirakami, Junichi Kato, Taku Mizutani, Takahiro Kochi, Hiroyasu Sakai, Masahito Shimizu
  • Organizer: The 14th Japan-Korea Joint Symposium on Cancer and Ageing Research
  • Int'l Joint Research