Elucidation of molecular mechanism through autophagy in carcinogenesis of hepatocellular carcinoma

• 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 肝細胞癌 / オートファジー / p62 / KEAP1 / Nrf2 / リン酸化p62 / 腫瘍増殖能亢進 / 抗癌剤耐性獲得 / HCV

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.

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。

Research Products

• [Journal Article] 肝細胞癌発癌過程におけるオートファジーを介した分子制御機構の解明 (2017)
  • Author(s): 坂田純、廣瀬雄己、齊藤哲也、小松雅明、若井俊文
  • Journal Title: Medical Science Digest Volume: 43 Pages: 331-333
  • Peer Reviewed
• [Journal Article] p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming (2016)
  • Author(s): Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T et al.
  • Journal Title: Nature Commun Volume: 7 Issue: 1 Pages: 12030-12030
  • DOI: 10.1038/ncomms12030
  • Peer Reviewed / Open Access / Int'l Joint Research