RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state.
Springer Science and Business Media LLC
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Belenguer, G., Mastrogiovanni, G., Pacini, C., Hall, Z., Dowbaj, A. M., Arnes-Benito, R., Sljukic, A., et al. (2022). RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-021-27923-z
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.
Liver, Hepatocytes, Animals, Humans, Mice, Carcinoma, Hepatocellular, Liver Neoplasms, Fatty Liver, Hepatomegaly, Hyperplasia, Ubiquitin-Protein Ligases, Prognosis, Liver Regeneration, Cell Differentiation, Cell Proliferation, Gene Expression Regulation, Gene Deletion, Adult, Lipid Metabolism, Lipid Droplets, Lipidomics
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
Wellcome Trust (104151/Z/14/Z)
European Commission (608180)
External DOI: https://doi.org/10.1038/s41467-021-27923-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334218
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/