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

Germán Belenguer, Gianmarco Mastrogiovanni, Clare Pacini, Zoe Hall, Anna M. Dowbaj, Robert Arnes-Benito, Aleksandra Sljukic, Nicole Prior, Sofia Kakava, Charles R. Bradshaw, Susan Davies, Michele Vacca, Kourosh Saeb-Parsy, Bon-Kyoung Koo and Meritxell Huch ()
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Germán Belenguer: The Max Planck Institute of Molecular Cell Biology and Genetics
Gianmarco Mastrogiovanni: University of Cambridge
Clare Pacini: Wellcome Sanger Institute
Zoe Hall: Imperial College London
Anna M. Dowbaj: The Max Planck Institute of Molecular Cell Biology and Genetics
Robert Arnes-Benito: The Max Planck Institute of Molecular Cell Biology and Genetics
Aleksandra Sljukic: The Max Planck Institute of Molecular Cell Biology and Genetics
Nicole Prior: The Max Planck Institute of Molecular Cell Biology and Genetics
Sofia Kakava: The Max Planck Institute of Molecular Cell Biology and Genetics
Charles R. Bradshaw: University of Cambridge
Susan Davies: Cambridge University Hospitals NHS Foundation Trust
Michele Vacca: University of Cambridge
Kourosh Saeb-Parsy: University of Cambridge and NIHR Cambridge Biomedical Research Centre
Bon-Kyoung Koo: Vienna Biocenter (VBC)
Meritxell Huch: The Max Planck Institute of Molecular Cell Biology and Genetics

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27923-z

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