Elucidation of molecular mechanism through autophagy in carcinogenesis of hepatocellular carcinoma

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10565
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Niigata University
• Principal Investigator: Sakata Jun 新潟大学, 医歯学系, 講師 (70447605)
• Co-Investigator(Kenkyū-buntansha): 小林 隆 新潟大学, 医歯学総合病院, 講師 (40464010) ; 若井 俊文 新潟大学, 医歯学系, 教授 (50372470)
• Research Collaborator: HIROSE Yuki ; MIURA Kohei ; ISHIKAWA Hirosuke ; SUDO Natsuru ; ANDO Takuya
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 肝細胞癌 / オートファジー / p62 / KEAP1 / Nrf2

Outline of Final Research Achievements

p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. We revealed the molecular mechanism of p62/Sqstm1-dependent malignant progression in carcinogenesis of hepatocellular carcinoma (HCC), and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against HCC. Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus.

Free Research Field

外科腫瘍学、消化器外科学

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的意義は、オートファジーやNRF2の研究の中でも、肝細胞癌（HCC）に焦点を当ててp62-KEAP1-NRF2経路活性化の意義を明らかにした点である。また、本研究の結果は、リン酸化p62およびKEAP1の相互作用を標的としたHCC、特にHCV陽性HCCに対する創薬事業にもフィードバックできる可能性があると考えている。