Investigation of the mechanisms of accelerated liver carcinogenesis caused by p53 over-activation.

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17432
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Osaka University
• Principal Investigator: Makino Yuki 大阪大学, 医学系研究科, 特任助教(常勤) (60771334)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: p53 / 肝発癌 / 肝前駆細胞

Outline of Final Research Achievements

In hepatocytes in chronic liver disease patients, tumor-suppressor p53 is constitutively activated. In our previous analysis, we have revealed that p53 activation increased hepatocarcinogenesis in liver cancer model mice. We investigated its mechanisms in the present study.Over-activation of hepatocyte p53 caused liver injury via increased hepatocyte apoptosis and senescence, leading to the emergence of liver progenitor cells. Tumors were histologically spreading from liver progenitor cells. Organoids generated from liver progenitor cells showed tumor-formation ability. These findings suggested that liver progenitor cells were the origin of liver tumors. The present study revealed that over-activation of hepatocyte p53 accelerated liver carcinogenesis originating from liver progenitor cells. Activated p53 could be a novel therapeutic target to prevent liver carcinogenesis in chronic liver disease patients.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

p53は代表的な癌抑制遺伝子であるが、本研究課題では肝細胞のp53が過剰に活性化すると逆に発癌が促進されることが示され、従来よく知られてきたp53の新たな側面を明らかにしたという点において大きな学術的意義を有する。
さらに本研究課題により、活性化したp53が慢性肝疾患患者における肝発癌予防の治療標的になることが示された。慢性肝疾患患者の肝発癌予防のためには、ウイルス性肝炎、アルコール性肝炎等の原疾患の治療以外に有効な方法がないのが現状であり、本研究課題によりこれまでにない新たな肝発癌予防法の開発に繋がる可能性があり、臨床的意義にも富んでいる。