Are activated stellate cells producing Cytoglobin directly involved in hepatocarcinogenesis?

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03641
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Osaka City University
• Principal Investigator: Kawada Norifumi 大阪市立大学, 大学院医学研究科, 教授 (30271191)
• Co-Investigator(Kenkyū-buntansha): 松原 三佐子 (佐藤三佐子) 大阪市立大学, 大学院医学研究科, 特任講師 (00635120) ; LE THITHANHTHUY 大阪市立大学, 大学院医学研究科, 特任講師 (10572175)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 肝星細胞 / 肝線維化 / Cytoglobin / コラーゲン / TGF-β / ROS

Outline of Final Research Achievements

CYGB is a respiratory protein that acts as a scavenger of reactive oxygen species (ROS) and protects cells from oxidative DNA damage. Cygb-overexpressing mice exhibited reduced liver inflammation and fibrosis, but high levels of quiescent HSCs compared to wild-type mice following 10 weeks of thioacetamide (TAA) induced advanced liver fibrosis. Similarly, Cygb-overexpressing mice showed attenuation of liver damage, fibrosis and ROS formation induced by 16 weeks of choline deficient amino acid define diet (CDAA) feeding or 12 months after diethylnitrosamine (DEN) treatment. We further found that the cytokine TGF-β1 downregulates human CYGB expression. In culture, TGF-β1-pretreated human HSCs exhibited lower CYGB levels - together with increased NADPH oxidase 4 expression leading to oxidative DNA damage in activated hepatic stellate cells - and were primed for H2O2-triggered -OH production and 8-OHdG generation; overexpression of human CYGB in human HSCs reversed these effects.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

これまで上皮細胞ばかりに焦点が集められていた発がんの分子機構について、間質細胞の重要性をグロビン蛋白との絡みで研究できれば、新たなパラダイムが広がる。肝がんは高度線維化や肝硬変を母地に発生するため、HSCsや筋線維芽細胞のがん発生における役割をCYGBと絡めて研究する意義は大きい。さらに、本研究を通じて肝脱線維化剤が開発されれば、治療法のない肝硬変に対して一矢を報いることになり臨床医学的にも極めて有用で、社会貢献度が高い。