Analysis of base excision repair abnormality in chronic inflammation-mediated hepatocarcinogenesis

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15938
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: ESO Yuji 京都大学, 医学研究科, 医員 (60760585)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 肝細胞癌 / DNA修復 / microRNA

Outline of Final Research Achievements

Hepatocellular carcinoma is known to occur in the background of chronic hepatitis and cirrhosis. However, the mechanism of inflammation-mediated hepatocarcinogenesis is still not clear enough. In this study, we aimed to clarify the role and mechanism of DNA repair abnormalities induced by chronic hepatitis in hepatocarcinogenesis.
First, we stimulated hepatocytes with various inflammatory cytokines, and analyzed for changes in the expression of DNA repair-related genes. As a result, the expression level of UNG mRNA, which is important for base excision repair, was significantly decreased. Furthermore, UNG mRNA expression was significantly reduced in the clinical samples of chronic hepatitis and liver cirrhosis. In addition, it has been suggested that inflammation-induced upregulation of microRNA-18a may be involved in the regulation of UNG mRNA expression.

Free Research Field

肝細胞癌

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌は臨床的に慢性肝炎～肝硬変を背景に発生することは広く知られているが、その発癌機序については未だ十分明らかではなかった。我々は以前、炎症によるDNA編集酵素の異所性発現による変異の導入・蓄積が肝発癌に寄与していることを明らかにしたが、本研究ではさらに、炎症により惹起されるDNA修復システムの異常により、遺伝子変異が蓄積されやすい状況になっている可能性が示唆された。本研究成果は、慢性肝炎からの肝発癌のみならず、他臓器における炎症発癌メカニズムのさらなる解明および治療戦略研究に繋がる可能性があるものと考えられる。