The development of novel therapy for hepatocellular carcinoma using RXR-alpha genetically modified mice

• Project/Area Number: 15K19320
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: Sakai Hiroyasu 岐阜大学, 医学部附属病院, 助教 (40738259)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肝細胞癌 / レチノイド / RXRα / 核内受容体 / 肝化学発癌

Outline of Final Research Achievements

The role of phosphorylated-RXRa (p-RXRa) on the development of liver tumorigenesis was investigated by using RXRa genetically modified mice. The transgenic mice were more susceptible to the treatment of diethylnitrosamine (DEN), and developed more liver tumors compared to the control mice. In addition, liver tumors observed in the transgenic mice had more PCNA positive cells, indicating that those tumors had high proliferative capacity. Besides, increased mRNA and protein expressions of cyclin D1 were observed in transgenic liver tumors, and the protein expressions of either p-Rb or PCNA, both of which are the downstream targets of cyclin D1, were also increased in those liver tumors. Interestingly, the transgenic liver tumors had more b-catenin protein expression, which regulates the expression of cyclin D1. Thus, these results indicate that the p-RXRa is associated with the development of DEN-induced liver tumorigenesis by promoting b-catenin/cyclin D1 signaling pathway.

Research Products

• [Journal Article] Preventative Effects of Pentoxifylline on the Development of Colonic Premalignant Lesions in Obese and Diabetic Mice (2017)
  • Author(s): Fukuta K, Shirakami Y, Maruta A, Obara K, Iritani S, Nakamura N, Kochi T, Kubota M, Sakai H, Tanaka T, Shimizu M
  • Journal Title: Int J Mol Sci Volume: 18(2) Issue: 2 Pages: 413-413
  • DOI: 10.3390/ijms18020413
  • Peer Reviewed / Open Access
• [Journal Article] Catechins and Its Role in Chronic Disease (2016)
  • Author(s): Shirakami Y, Sakai H, Kochi T, Seishima M, Shimizu M
  • Journal Title: Adv Exp Med Biol Volume: 929 Pages: 67-90
  • Peer Reviewed
• [Journal Article] Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice. (2016)
  • Author(s): Miyazaki T, Shirakami Y, Kubota M, Ideta T, Kochi T, Sakai H, Tanaka T, Moriwaki H, Shimizu M.
  • Journal Title: Oncotarget Volume: - Issue: 9 Pages: 10448-10458
  • DOI: 10.18632/oncotarget.7249
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents. (2016)
  • Author(s): Sakai H, Shirakami Y, Shimizu M.
  • Journal Title: World J Gastroenterol Volume: 22(1) Issue: 1 Pages: 394-406
  • DOI: 10.3748/wjg.v22.i1.394
  • Peer Reviewed / Open Access
• [Journal Article] Preventive effects of astaxanthin on diethylnitrosamine-induced liver tumorigenesis in C57/BL/KsJ-db/db obese mice. (2016)
  • Author(s): Ohno T, Shimizu M, Shirakami Y, Miyazaki T, Ideta T, Kochi T, Kubota M, Sakai H, Tanaka T, Moriwaki H.
  • Journal Title: Hepatol Res. Volume: 46(3) Issue: 3 Pages: 201-209
  • DOI: 10.1111/hepr.12550
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Attenuates Hepatic Lipogenesis via AMPK Activation in Non-Alcoholic Fatty Liver Disease Model Mice. (2015)
  • Author(s): Ideta T, Shirakami Y, Miyazaki T, Kochi T, Sakai H, Moriwaki H, Shimizu M.
  • Journal Title: Int J Mol Sci. Volume: 16(12) Issue: 12 Pages: 29207-29218
  • DOI: 10.3390/ijms161226156
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Retinoid roles in blocking hepatocellular carcinoma. (2015)
  • Author(s): Shirakami Y, Sakai H, Shimizu M.
  • Journal Title: Hepatobiliary Surg Nutr. Volume: 4(4) Pages: 222-228
  • Peer Reviewed / Open Access
• [Journal Article] Chemopreventive potential of green tea catechins in hepatocellular carcinoma. (2015)
  • Author(s): Shimizu M, Shirakami Y, Sakai H, Kubota M, Kochi T, Ideta T, Miyazaki T, Moriwaki H.
  • Journal Title: Int J Mol Sci. Volume: 16(3) Issue: 3 Pages: 6124-6139
  • DOI: 10.3390/ijms16036124
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] The role of the phosphorylated RXR-alpha on cellular proliferation and liver tumorigenesis (2016)
  • Author(s): Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu
  • Organizer: AACR annual meeting 2016
  • Place of Presentation: ニューオーリンズ（アメリカ合衆国）
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] The role of the phosphorylated RXRα on Diethylnitrosamine-induced liver tumorigenesis in mice (2016)
  • Author(s): Hiroyasu Sakai, Yasuhiro Yamada, Yohei Shirakami, Akira Hara, and Masahito Shimizu
  • Organizer: APASL 2016 in Tokyo
  • Place of Presentation: グランドプリンスホテル新高輪（東京）
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] The role of the phosphorylated RXRα on Diethylnitrosamine-induced liver tumorigenesis in mice (2015)
  • Author(s): Hiroyasu Sakai, Yasuhiro Yamada, Yohei Shirakami, Akira Hara, and Masahito Shimizu
  • Organizer: 第3回国際レチノイド研究会
  • Place of Presentation: 岐阜グランドホテル（岐阜）
  • Year and Date: 2015-10-21
  • Int'l Joint Research
• [Presentation] The role of the phosphorylated RXRα on Diethylnitrosamine-induced liver tumorigenesis in mice (2015)
  • Author(s): Hiroyasu Sakai, Yasuhiro Yamada, Yohei Shirakami, Akira Hara, and Masahito Shimizu
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-10-08
• [Presentation] The role of the phosphorylated RXRα on cellular proliferation and liver tumorigenesis in mice (2015)
  • Author(s): Hiroyasu Sakai, Yohei Shirakami, and Masahito Shimizu
  • Organizer: 2015 AACR annual meeting
  • Place of Presentation: フィラデルフィア（アメリカ合衆国）
  • Year and Date: 2015-04-18
  • Int'l Joint Research