1. RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state.
- Author
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Belenguer G, Mastrogiovanni G, Pacini C, Hall Z, Dowbaj AM, Arnes-Benito R, Sljukic A, Prior N, Kakava S, Bradshaw CR, Davies S, Vacca M, Saeb-Parsy K, Koo BK, and Huch M
- Subjects
- Adult, Animals, 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 pathology, Liver Neoplasms pathology, Mice, Prognosis, Carcinoma, Hepatocellular metabolism, Liver metabolism, Liver Neoplasms metabolism, Liver Regeneration, Ubiquitin-Protein Ligases metabolism
- 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., (© 2022. The Author(s).)
- Published
- 2022
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