Pathogenesis of Hepatocellular Carcinoma with DNA Repair Abnormalities and Response to Immune Checkpoint Inhibition Therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07912
• 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: Kyoto University
• Principal Investigator: Eso Yuji 京都大学, 医学研究科, 客員研究員 (60760585)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 肝細胞癌 / ミスマッチ修復

Outline of Final Research Achievements

Tumors defective in DNA mismatch repair (dMMR) are known to differ from normal cancers in terms of response to therapy. We previously reported that inflammatory stimuli downregulate the expression of the mismatch repair gene MSH2 in hepatocytes, which may contribute to carcinogenesis. In this study, we aimed to elucidate the role of MSH2 in the inflammatory hepatocarcinogenesis process by creating an animal model in which genetically engineered mice lacking MSH2 were subjected to chronic hepatitis stimulation. The results showed that deletion of MSH2 promotes hepatocarcinogenesis and that the resulting tumors have characteristics of dMMR. The results also suggest that MSH2 may contribute to carcinogenesis inhibition not only by DNA repair but also by regulating cell proliferation.

Free Research Field

肝細胞癌

Academic Significance and Societal Importance of the Research Achievements

MSH2遺伝子が欠失にすることにより、肝発癌が促進され、生じた腫瘍はdMMRの特徴を有することが明らかとなった。またMSH2はDNAミスマッチ修復のみならず、DNA damage sensorとして細胞増殖の制御にも関わることにより、発癌抑制に寄与する可能性が示唆された。