Nuclear IKKbeta regulates DEN-induced hepatic carcinogenesis through the suppression of DNA-binding activity of HNF4alpha

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K18419
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Hiroshima Jogakuin University (2017-2018); Hiroshima University (2016)
• Principal Investigator: TSUCHIYA Yoshihiro 広島女学院大学, 人間生活学部, 准教授 (90611301)
• Research Collaborator: KAMATA Hideaki 広島大学, 医歯薬保健学研究院, 准教授 (10233925)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 肝炎 / 肝がん / 化学発がん

Outline of Final Research Achievements

Gene analysis revealed that expression of hepatic cytochrome P450 (CYP) enzymes including Cyp2E1, which mediates the activation of chemical carcinogens, was markedly reduced in Tg-IKKβΔhep. Injection of TNFα- or IL-1β in mice markedly suppress the expression of cyp genes in livers. Although HNF4α express normally in liver, its binding to the chromatin was prevented in livers in Tg-IKKβΔhep and mice injected with TNFα or IL-1β. These results suggest that suppression of Cyp2E1 expression reduced DEN induced hepatocarcinogenesis in inflammatory conditions.

Free Research Field

生化学　分子生物学

Academic Significance and Societal Importance of the Research Achievements

一般に炎症は発がんを亢進するが、逆に炎症による組織障害が化学発がんの抑制につながる新たなケースが本実験により示された。炎症による肝特異的転写因子HNF4αの活性抑制が、シトクロムp450などの代謝系遺伝子の発現抑制をもたらし、これが発がん抑制に至ることまで解明した。この研究成果は、炎症による発がん制御において新しい分子機構の解明につながるものであると考えられた。