P62 Promotes Survival and Hepatocarcinogenesis in Mice with Liver-Specific NEMO Ablation.

Abstract

Simple SummaryChronic liver injury is a predisposing factor for hepatocellular carcinoma (HCC) development. p62-mediated Nrf2 overactivation has been shown to drive liver injury and HCC in mice with hepatic impairment of autophagy. Here, we addressed the role of this pathway in a liver disease mouse model that does not exhibit inherent autophagy defect. Genetically-induced Nrf2 overactivation without concomitant strong increase in p62 expression did not aggravate liver injury and hepatocarcinogenesis. In contrast, p62-driven Nrf2 overactivation was prominent in liver tumors of mice that expressed a p62 mutant and showed enhanced hepatocarcinogenesis. Moreover, a negative correlation was observed between p62/Nrf2high liver tumors and the autophagosome marker LC3, suggesting that acquired autophagy defects precede the activation of this pro-tumorigenic pathway. Our results suggest that autophagy activators or Nrf2 inhibitors could be considered therapeutically in cases of p62/Nrf2high liver tumors.SQSTM1/p62 is a multitasking protein that functions as an autophagy receptor, but also as a signaling hub regulating diverse cellular pathways. p62 accumulation in mice with autophagy-deficient hepatocytes mediates liver damage and hepatocarcinogenesis through Nrf2 overactivation, yet the role of the p62-Keap1-Nrf2 axis in cell death and hepatocarcinogenesis in the absence of underlying autophagy defects is less clear. Here, we addressed the role of p62 and Nrf2 activation in a chronic liver disease model, namely mice with liver parenchymal cell-specific knockout of NEMO (NEMOLPC-KO), in which we demonstrate that they show no inherent autophagy impairment. Unexpectedly, systemic p62 ablation aggravated the phenotype and caused early postnatal lethality in NEMOLPC-KO mice. Expression of a p62 mutant (p62ΔEx2-5), which retains the ability to form aggregates and activate Nrf2 signaling, did not cause early lethality, but exacerbated hepatocarcinogenesis in these mice. Our immunohistological and molecular analyses showed that the increased tumor burden was only consistent with increased expression/stability of p62ΔEx2-5 driving Nrf2 hyperactivation, but not with other protumorigenic functions of p62, such as mTOR activation, cMYC upregulation or increased fibrosis. Surprisingly, forced activation of Nrf2 per se did not increase liver injury or tumor burden in NEMOLPC-KO mice, suggesting that autophagy impairment is a necessary prerequisite to unleash the Nrf2 oncogenic potential in mice with autophagy-competent hepatocytes.