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

RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state
RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state
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.
2041-1723
Belenguer, Germán
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Mastrogiovanni, Gianmarco
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Pacini, Clare
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Hall, Zoe
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Dowbaj, Anna M.
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Arnes-Benito, Robert
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Sljukic, Aleksandra
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Prior, Nicole
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Kakava, Sofia
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Bradshaw, Charles R.
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Davies, Susan
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Vacca, Michele
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Saeb-Parsy, Kourosh
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Koo, Bon-Kyoung
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Huch, Meritxell
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Belenguer, Germán
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Mastrogiovanni, Gianmarco
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Pacini, Clare
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Hall, Zoe
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Dowbaj, Anna M.
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Arnes-Benito, Robert
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Sljukic, Aleksandra
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Prior, Nicole
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Kakava, Sofia
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Bradshaw, Charles R.
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Davies, Susan
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Vacca, Michele
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Saeb-Parsy, Kourosh
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Koo, Bon-Kyoung
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Huch, Meritxell
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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 and Huch, Meritxell (2022) RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state. Nature Communications, 13 (1), [334]. (doi:10.1038/s41467-021-27923-z).

Record type: Article

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.

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Published date: 17 January 2022
Additional Information: Funding Information: M.H. is funded by a Lise Meitner Max Planck Research Group Leader award (LMA MOZG0001). Part of this work was funded by a Horizon 2020 grant (LSFM4LIFE) and a Wellcome Trust Sir Henry Dale Fellowship from the Wellcome Trust and Royal Society (104151/Z/14/Z) awarded to M.H. G.M. and B.-K.K. were funded by a Marie Curie Initial Training Network (Marie Curie ITN WntsApp 608180). We acknowledge core funding from the MPI-CBG and the Gurdon Institute WT, 092096 and CRUK, C6946/A14492. Also, we would like to acknowledge the Gurdon Institute and Cambridge Stem Cell Institute Animal facilities and the MPI-CBG Imaging and MPI-CBG Image Analysis Facilities; Dr Maike Paramor (Cambridge Stem Cell Institute) and Mr Kay Harnish of the Gurdon Institute genomics facility for assistance with sequencing; Dr Andre Nadler, from MPI-CBG, for constructive discussions; Dr Laura Broutier, Dr Luigi Aloia and Lucia Cordero-Espinoza for experimental help; Sara Seifert for help with hepatocyte isolations; Dr Holger Kramer and Dr Joao Mokochinski (MRC London Institute of Medical Sciences) for access to MS instrumentation; and, additionally, Professor Hans Clevers and Professor Pierre Chambon for sharing the Rnf43-flx/Znrf3-flx and AlbCre-ERT2 mice, respectively. Publisher Copyright: © 2022, The Author(s).

Identifiers

Local EPrints ID: 454237
URI: http://eprints.soton.ac.uk/id/eprint/454237
ISSN: 2041-1723
PURE UUID: 0b8d7980-a42c-41e3-b569-5c6b79fc8687
ORCID for Nicole Prior: ORCID iD orcid.org/0000-0003-2856-7052

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Date deposited: 03 Feb 2022 17:46
Last modified: 03 Dec 2022 02:59

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Contributors

Author: Germán Belenguer
Author: Gianmarco Mastrogiovanni
Author: Clare Pacini
Author: Zoe Hall
Author: Anna M. Dowbaj
Author: Robert Arnes-Benito
Author: Aleksandra Sljukic
Author: Nicole Prior ORCID iD
Author: Sofia Kakava
Author: Charles R. Bradshaw
Author: Susan Davies
Author: Michele Vacca
Author: Kourosh Saeb-Parsy
Author: Bon-Kyoung Koo
Author: Meritxell Huch

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