p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells

• DOI: 10.1016/j.ccell.2016.04.006
• Publication Date: 2016-05-21T04:27:31Z
• Authors: Atsushi Umemura; Feng He; Koji Taniguchi; Hayato Nakagawa; Shinichiro Yamachika; Joan Font-Burgada; Zhenyu Zhong; Shankar Subramaniam; Sindhu Raghunandan; Angeles Duran; Juan F. Linares; Miguel Reina-Campos; Shiori Umemura; Mark A. Valasek; Ekihiro Seki; Kanji Yamaguchi; Kazuhiko Koike; Yoshito Itoh; Maria T. Diaz-Meco; Jorge Moscat; Michael Karin
• Keywords: Liver Cancer; 0301 basic medicine; Carcinoma, Hepatocellular; Cell Survival; NF-E2-Related Factor 2; Oncology and Carcinogenesis; Chronic Liver Disease and Cirrhosis; Mice, Transgenic; Mechanistic Target of Rapamycin Complex 1; Transgenic; Proto-Oncogene Proteins c-myc; Experimental; Mice; 03 medical and health sciences; Rare Diseases; Neoplasms; Sequestosome-1 Protein; Animals; Humans; Diethylnitrosamine; Oncology & Carcinogenesis; Cancer; Neoplastic; Biomedical and Clinical Sciences; Liver Disease; TOR Serine-Threonine Kinases; Carcinoma; Liver Neoplasms; Neurosciences; Hepatocellular; Oncology and carcinogenesis; Neoplasms, Experimental; Up-Regulation; Gene Expression Regulation, Neoplastic; Gene Expression Regulation; Biochemistry and cell biology; Multiprotein Complexes; Neoplastic Stem Cells; Digestive Diseases

p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation 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 ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death.