RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state

Nat Commun. 2022 Jan 17;13(1):334. doi: 10.1038/s41467-021-27923-z.

Abstract

RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Differentiation
  • Cell Proliferation
  • Fatty Liver / pathology
  • Gene Deletion
  • Gene Expression Regulation
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hepatomegaly / pathology
  • Humans
  • Hyperplasia
  • Lipid Droplets / metabolism
  • Lipid Metabolism / genetics
  • Lipidomics
  • Liver / metabolism*
  • Liver / pathology
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Regeneration*
  • Mice
  • Prognosis
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • RNF43 protein, human
  • Ubiquitin-Protein Ligases
  • ZNRF3 protein, human