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

Author

Listed:
  • Germán Belenguer

    (The Max Planck Institute of Molecular Cell Biology and Genetics)

  • Gianmarco Mastrogiovanni

    (University of Cambridge
    University of Cambridge
    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
    University of Bari “Aldo Moro”)

  • 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
    University of Cambridge
    University of Cambridge)

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.

Suggested Citation

  • 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 & M, 2022. "RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27923-z
    DOI: 10.1038/s41467-021-27923-z
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    References listed on IDEAS

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    1. Bi-Sen Ding & Daniel J. Nolan & Jason M. Butler & Daylon James & Alexander O. Babazadeh & Zev Rosenwaks & Vivek Mittal & Hideki Kobayashi & Koji Shido & David Lyden & Thomas N. Sato & Sina Y. Rabbany , 2010. "Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration," Nature, Nature, vol. 468(7321), pages 310-315, November.
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