Intestinal dysbiosis increases the risk of hepatocellular carcinoma - the study for protective mechanism against carcinoma using new animal models

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02884
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Yamamoto Masakazu 東京女子医科大学, 医学部, 教授 (60220498)
• Co-Investigator(Kenkyū-buntansha): 柳川 徹 筑波大学, 医学医療系, 教授 (10312852) ; 有泉 俊一 東京女子医科大学, 医学部, 准教授 (40277158) ; 徳重 克年 東京女子医科大学, 医学部, 教授 (60188729) ; 蕨 栄治 筑波大学, 医学医療系, 講師 (70396612) ; 正田 純一 筑波大学, 医学医療系, 教授 (90241827)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: NASH / 肝癌 / 腸内細菌叢 / LPS / p62 / Nrf2 / ゲノム解析 / 遺伝子改変マウス

Outline of Final Research Achievements

p62 and Nrf2 double knock-out mice exhibit the development of NASH and hepatocellular carcinoma (HCC) at the senile state. Influence of a high-fat diet (HFD) on the development of liver pathology was investigated. In the genomic analysis, HDF induced the decreased alpha-diversity of intestinal bacteria. The expression levels of LPS-binding protein were higher in the mice with HCC than in those without HCC. To explore the role of p62 in human NASH and HCC, tissue and cell-specific p62 gene rescue mice were generated. p62 in hepatocytes was considered to play a protective role against the development of NASH and HCC. Activation of p62 could be a promising target for the prevention and treatment of NASH and HCC.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

NASHは肝硬変，肝癌へ進行する慢性肝疾患である．しかし，その発症機序は未解明であり，NASH進行および肝癌発生を阻止するための薬物治療も確立していない．本研究は，DKOマウスに高脂肪食を摂餌させヒトNASHおよび肝癌に類似する新規モデルを作製したことにより，NASH-肝発癌のメカニズム解明に貢献すると考えられる．肝細胞のp62がNASHと肝癌に対して防御的な役割を果たすことを見出したことにより，p62が新しいNASHの治療標的と成り得る可能性を示した点で，将来的なNASH治療開発のための研究として意義が大きい．