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

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. [Display omitted] •p62 in preneoplastic lesions is important for HCC development regardless of etiology•Ectopic p62 expression is sufficient for HCC induction in autophagy-competent liver•p62 exerts its oncogenic activity via NRF2 and mTORC1 but not via ubiquitin binding•p62 promotes survival and expansion of ROS-containing HCC-initiating cells Umemura et al. employ several mouse models of HCC to demonstrate that p62 facilitates activation of NRF2 and mTORC1 and is essential for HCC initiation. High levels of p62 accumulation in non-tumor liver tissue in early-stage HCC patients undergoing curative ablation correlates with reduced overall survival.