Loss of RNF43/ZNRF3 predisposes to Hepatocellular carcinoma by impairing liver regeneration and altering liver fat metabolism

ABSTRACT: The homologous E3 ubiquitin ligases RNF43/ZNRF3 negatively regulate WNT signalling activation. Recently, both genes have been found mutated in several types of cancers. Specifically, loss-of-function mutations result in adenoma formation in mouse small intestine. However, their role in liver pathology and cancer has not been explored yet. Here, we describe that hepatocyte-specific deletion of Rnf43/Znrf3 results in altered lipid metabolism and steatohepatitis, in the absence of exogenous dietary fat supplementation, with a remarkable increase in unsaturated lipids. Upon liver injury, Rnf43/Znrf3 deletion results in impaired hepatocyte regeneration and liver cancer, subsequent to an imbalance between differentiation and proliferation. Using three different liver organoid models (hepatocyte-, hepatoblast- and ductal cell-derived organoids) we demonstrate that the hepatocyte differentiation defects and the lipid metabolic alterations are, at least in part, cell-autonomous. Remarkably, hepatocellular carcinoma patients with mutations in either or both genes or in other WNT pathway components also present altered hepatic lipid metabolism and non-alcoholic steatohepatitis (NASH) profiles. Our findings imply that hyperactivation of WNT signaling through the RNF43/ZNRF3 module predisposes to liver cancer by impairing hepatocyte differentiation and altering the lipid metabolic ground-state of the liver. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 or WNT mutated individuals at risk of developing fatty liver and/or liver cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE133213 | GEO | 2021/12/10

REPOSITORIES: GEO