Universität zu Köln

Kondylis, Vangelis ORCID: 0000-0002-6970-8731, Schneider, Farina, Schorn, Fabian, Oikonomou, Nikos, Straub, Beate Katharina, Werner, Sabine, Rosenstiel, Philip ORCID: 0000-0002-9692-8828 and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2022). p62 Promotes Survival and Hepatocarcinogenesis in Mice with Liver-Specific NEMO Ablation. Cancers, 14 (10). BASEL: MDPI. ISSN 2072-6694

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kondylis, Vangelis UNSPECIFIED orcid.org/0000-0002-6970-8731 UNSPECIFIED Schneider, Farina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schorn, Fabian UNSPECIFIED UNSPECIFIED UNSPECIFIED Oikonomou, Nikos UNSPECIFIED UNSPECIFIED UNSPECIFIED Straub, Beate Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Werner, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenstiel, Philip UNSPECIFIED orcid.org/0000-0002-9692-8828 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-684636
DOI:	10.3390/cancers14102436
Journal or Publication Title:	Cancers
Volume:	14
Number:	10
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; TRANSCRIPTION FACTOR NRF2; HEPATOCELLULAR-CARCINOMA; SIGNALING ADAPTER; AUTOPHAGY; ACTIVATION; DEFICIENT; P62/SQSTM1; STEATOHEPATITIS; TUMORIGENESIS Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68463