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

  • Belenguer, Germán
  • Mastrogiovanni, Gianmarco
  • Pacini, Clare
  • Hall, Zoe
  • Dowbaj, Anna M
  • Arnes-Benito, Robert
  • Sljukic, Aleksandra
  • Prior, Nicole
  • Kakava, Sofia
  • Bradshaw, Charles R
  • Davies, Susan
  • Vacca, Michele
  • Saeb-Parsy, Kourosh
  • Koo, Bon-Kyoung
  • Huch, Meritxell
Publication Date
Jan 17, 2022
Apollo - University of Cambridge Repository
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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.

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