p62 Promotes Survival and Hepatocarcinogenesis in Mice with Liver-Specific NEMO Ablation
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Date
2022-05-15
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Journal Article
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Abstract
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 autophagydeficient hepatocytes mediates liver damage and hepatocarcinogenesis through Nrf2 overactivation, yet the role of the p62-Keapl-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 NEMO(LPC-KO )mice. Expression of a p62 mutant (p624Ex2-5), 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 p624Ex2-5 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.
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published
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Journal / series
Volume
14 (10)
Pages / Article No.
2436
Publisher
MDPI
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Subject
IκB kinase (IKK) complex; autophagy; chronic liver disease; liver injury; hepatocarcinogenesis; Keap1-Nrf2 activation; genetic mouse models
Organisational unit
03520 - Werner, Sabine / Werner, Sabine