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

Cancer Cell. 2016 Jun 13;29(6):935-948. doi: 10.1016/j.ccell.2016.04.006. Epub 2016 May 19.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Cell Survival
  • Diethylnitrosamine / adverse effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Transgenic
  • Multiprotein Complexes / genetics
  • NF-E2-Related Factor 2 / genetics
  • Neoplasms, Experimental
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / drug effects
  • Proto-Oncogene Proteins c-myc / genetics
  • Sequestosome-1 Protein / genetics*
  • TOR Serine-Threonine Kinases / genetics
  • Up-Regulation*

Substances

  • MYC protein, human
  • Multiprotein Complexes
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Proto-Oncogene Proteins c-myc
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Diethylnitrosamine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1