The role of p62 in the HCC initiation and progression

• Project/Area Number: 15H06547
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Tumor biology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Umemura Atsushi 京都府立医科大学, 医学(系)研究科(研究院), 助教 (30759585)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肝癌 / p62 / NRF2 / mTOR / 癌 / 医療・福祉 / シグナル伝達 / 肝細胞癌

Outline of Final Research Achievements

p62 is a autophagy receptor and signaling protein that accumulates in premalignant liver diseases such as non-alcoholic steatohepatitis (NASH), and most hepatocellular carcinomas (HCCs). Although p62 has been shown to participate in cancer progression, its role in HCC development was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative treatment. High p62 expression is needed for activation of NRF2 and mTORC1, and protection of HCC-initiating cells from oxidative stress-induced death in chronic liver diseases.

Research Products

• [Int'l Joint Research] University of California, San Diego/Sanford Burnham Medical Institute(米国)
• [Int'l Joint Research] University of California, San Diego/sanford burnham研究所(米国)
• [Journal Article] Hepatic nucleotide binding oligomerization domain-like receptors pyrin domain-containing 3 inflammasomes are associated with the histologic severity of non-alcoholic fatty liver disease. (2017)
  • Author(s): Mitsuyoshi H, Yasui K, Hara T, Taketani H, Ishiba H, Okajima A, Seko Y, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Minami M, Itoh Y.
  • Journal Title: Hepatol Res Volume: - Issue: 13 Pages: 1459-1468
  • DOI: 10.1111/hepr.12883
  • Peer Reviewed
• [Journal Article] p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. (2016)
  • Author(s): Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, Linares JF, Reina-Campos M, Umemura S, Valasek MA, Seki E, Yamaguchi K, Koike K, Itoh Y, Diaz-Meco MT, Moscat J, Karin M.
  • Journal Title: Cancer Cell Volume: 29 Pages: 935-948
  • DOI: 10.1016/j.canlet.2017.04.002
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genome-wide DNA methylation analysis in hepatocellular carcinoma. (2016)
  • Author(s): Yamada N, Yasui K, Dohi O, Gen Y, Tomie A, Kitaichi T, Iwai N, Mitsuyoshi H, Sumida Y, Moriguchi M, Yamaguchi K, Nishikawa T, Umemura A, Naito Y, Tanaka S, Arii S, Itoh Y.
  • Journal Title: Oncol Rep. Volume: 35 Issue: 4 Pages: 2228-2236
  • DOI: 10.3892/or.2016.4619
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression. (2016)
  • Author(s): Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, Hara T, Okajima A, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Kanemasa K, Yasui K, Imai S, Shimada K, Itoh Y.
  • Journal Title: Hepatol Res Volume: - Issue: 11 Pages: 1083-1092
  • DOI: 10.1111/hepr.12840
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma. (2016)
  • Author(s): Moriguchi M, Umemura A, Itoh Y.
  • Journal Title: Clin J Gastroenterol Volume: 9 Issue: 4 Pages: 184-190
  • DOI: 10.1007/s12328-016-0670-7
• [Journal Article] 肝細胞癌とオートファジー (2016)
  • Author(s): 楳村敦詩、山口寛二、Michael Karin、伊藤義人
  • Journal Title: 肝胆膵 Volume: 73 Pages: 201-206
• [Journal Article] NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. (2016)
  • Author(s): Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR,McGeough MD, Ellisman MH, Seki E, Gustafsson AB, Hoffman HM, Diaz-Meco MT, Moscat J, Karin M.
  • Journal Title: Cell Volume: 164(5) Issue: 5 Pages: 896-910
  • DOI: 10.1016/j.cell.2015.12.057
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 肝発癌・進展における，mTORC1およびp62-Nrf2シグナルの役割 (2016)
  • Author(s): 楳村敦詩、山口寛二、伊藤義人
  • Organizer: 第52回日本肝臓学会総会（幕張）
  • Place of Presentation: 幕張
  • Year and Date: 2016-05-19
  • Int'l Joint Research
• [Presentation] The Effect of mTORC1 Inhibition on NAFLD and subsequent HCC Development (2016)
  • Author(s): Atsushi Umemura, Yoshito Itoh, Michael Karin.
  • Organizer: The international congress 2016, European Association for the Study of the Liver (EASL)
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-04-15
  • Int'l Joint Research
• [Presentation] 肝癌および慢性肝疾患の病態におけるmTORC1阻害の影響 (2015)
  • Author(s): 楳村敦詩、山口寛二、伊藤義人
  • Organizer: 第41回日本肝臓学会西部会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-12-03
• [Presentation] p62, a Key Regulator for Initiation and Development of HCC (2015)
  • Author(s): Atsushi Umemura, Yoshito Itoh, Maria T. Diaz-Meco, Jorge Moscat, and Michael Karin
  • Organizer: AASLD Liver meeting 2015
  • Place of Presentation: Moscone Center in San Francisco
  • Year and Date: 2015-11-17
  • Int'l Joint Research