Functional analysis of new therapeutic target factors for tumorigenesis and recurrence with liver fibrosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17485
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kanazawa University
• Principal Investigator: Okada Hikari 金沢大学, 医薬保健学総合研究科, 特任助教 (50788916)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 肝発がん / 肝線維化 / PKM / NCID

Outline of Final Research Achievements

The applicant confirmed from the expression analysis that the expression of both PKM1 and PKM2, which are PKM variants, increases with the progression of hepatic fibrosis and the malignancy of hepatocellular carcinoma. PKM1 enhanced hepatic fibrosis by transforming hepatic stellate cells into myofibroblasts. PKM2 was shown to form a complex with the intracellular domain NICD of Notch1 in liver cancer cells. And it was shown that this complex has a role of increasing the malignancy of hepatocellular carcinoma through CSL in the nucleus.　 From these research results, it was clarified that a therapeutic strategy that inhibits the expression of both PKM1 and PKM2 is more effective than PKM2 alone for the pathological condition of liver carcinogenesis based on liver fibrosis.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

肝硬変を背景とした肝細胞癌患者では、根治的治療後でも肝細胞癌が高率に再発し、再発率は年間約20-25%、5年では70%以上に上ることから肝細胞癌の再発抑制が治療上極めて重要な課題である。そのため、肝線維化・肝硬変による肝発がん機序を解明し、新規治療法につながる基礎研究が重要である。今回の研究成果から、肝線維化病態から肝発がん過程におけるPKM1とPKM2の発現制御機序の一端を解明することができ、肝線維化及び肝発がん・再発に対する新規治療標的の可能性を示せた。