Cell fate analysis of Zone 3 hepatocytes and their potential as a cancer origin

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07887
• 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: The University of Tokyo
• Principal Investigator: Wake Taijiro 東京大学, 医学部附属病院, 届出研究員 (60895267)
• Co-Investigator(Kenkyū-buntansha): 中川 勇人 三重大学, 医学系研究科, 教授 (00555609)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 肝細胞癌 / 発癌起源

Outline of Final Research Achievements

We established a method for persistent genetic labeling of Zone 3 hepatocytes using mice expressing CreERT under the Axin2 promoter (Axin2-CreERT). Our findings highlight four key points: ① There is a cell population in Zone 3 with high carcinogenic potential; ② Liver carcinogenesis is promoted by Wnt/β-catenin activation niche and potentially be suppressed by Wnt inhibitors; ③ Under liver injury, Axin2-expressing hepatocytes significantly contribute to liver regeneration and possesse high neoplastic potential; ④ The metabolic phenotype of hepatocellular carcinoma is acquired during the carcinogenic process, rather than from the site of cellullar origin.

Free Research Field

消化器病学

Academic Significance and Societal Importance of the Research Achievements

本研究のように、zone別の肝発癌リスクを解析した研究は非常に少なく、肝発癌過程を理解するうえで非常に重要な示唆を与える。また現在、肝発癌を予防する薬剤は存在しないが、今回の研究で示されたWnt/βカテニン活性化ニッチを標的とした肝発癌抑止策は、今後の臨床応用に向けてさらなる検討を行う価値があると考えられる。