Elucidation of the mechanism by which vascular endothelial cells are involved in liver carcinogenesis/recurrence

• Project/Area Number: 18K15777
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Department of Clinical Research, National Hospital Organization Kanazawa Medical Center (2019); Kanazawa University (2018)
• Principal Investigator: Nishikawa Masashi 独立行政法人国立病院機構(金沢医療センター臨床研究部), その他部局等, 研究員 (90794511)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝発がん / SVR / メチル化 / 血管内皮細胞

Outline of Final Research Achievements

We identified TMEM this time by comprehensive methylation analysis of the group achieving sustained viral response (SVR) and HCC group after achieving SVR, and expression level analysis. TMEM is a novel gene of unknown function. TMEM was found to be expressed in tumor-infiltrating vascular endothelial cells, and the recurrence-free period of liver cancer was significantly short in the high TMEM-expressing group. It was confirmed that TMEM-overexpressing vascular endothelial cells significantly promote tumor formation. TMEM has been shown to enhance tumorigenesis via the ER stress pathway. It was suggested that TMEM could be a therapeutic target for liver carcinogenesis and hepatocellular carcinoma.

Academic Significance and Societal Importance of the Research Achievements

C型肝炎ウイルス排除達成（SVR）後の肝発がんが社会的問題となっている。SVR後肝組織を用いた網羅的メチル化解析により今回同定したTMEMは新規かつ機能未知の遺伝子であるが、我々の研究によりTMEMが腫瘍浸潤血管内皮細胞に発現し、肝発がんに関与していることを確認した。したがって、TMEMは肝発がん及び肝細胞癌の治療標的になり得ることが示唆され、臨床応用により治療へとつなげる可能性があると考えられた。

Research Products

• [Presentation] C 型肝炎ウイルス排除後肝癌における背景肝メチル化と肝線維化 (2019)
  • Author(s): 西川昌志、本多政夫、金子周一
  • Organizer: 第105回消化器病学会総会 WS12-8
• [Presentation] Genome-wide methylation analysis identified a new intrahepatic vascular endothelial marker associated with induction of tumorigenesis after successful eradication of HCV (2019)
  • Author(s): Masashi Nishikawa, Masao Honda, Hikari Okada, Kazunori Kawaguchi, Rika Horii, Tetsuro Shimakami, Kuniaki Arai, Taro Yamashita, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, and Shuichi Kaneko
  • Organizer: AASLD2019
  • Int'l Joint Research
• [Presentation] C型肝炎ウイルス排除後肝癌における背景肝メチル化測定の有用性 (2018)
  • Author(s): 西川昌志、本多政夫、金子周一
  • Organizer: 肝癌研究会 PD2-10