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.
Belenguer, Germán
6c9599c1-ff93-4211-836d-3d33734c873d
Mastrogiovanni, Gianmarco
8a9ef419-8ff8-48b7-a2f1-5268fc3273a9
Pacini, Clare
aedd6b0b-54c8-49fb-a4ff-df17592ca460
Hall, Zoe
90f578da-ee5a-4a60-bced-b49cc0cbc59c
Dowbaj, Anna M.
bcc5944c-e1c5-42cf-90d0-de20f550ddce
Arnes-Benito, Robert
a15d8267-9570-4411-8ef1-7c4c465bb499
Sljukic, Aleksandra
71f91178-ea05-4ac5-907a-db5a2ee4299c
Prior, Nicole
27851f03-6041-4409-a15c-a2a164b883e0
Kakava, Sofia
8a228b82-013d-4351-8015-8675ea517967
Bradshaw, Charles R.
14ac7ee8-b608-4335-bfb7-2246add5a939
Davies, Susan
6878890f-b27b-411a-9157-b74dca77185f
Vacca, Michele
9e4fa176-34fc-41b4-87b5-ea61a4f36fd8
Saeb-Parsy, Kourosh
598a9eb8-f4b0-45e4-ac27-679cff7d2919
Koo, Bon-Kyoung
df7efb66-cd4e-4e86-8a57-4116130e8fb1
Huch, Meritxell
defdc21f-6ca2-4a97-ab38-436adce9d37c
17 January 2022
Belenguer, Germán
6c9599c1-ff93-4211-836d-3d33734c873d
Mastrogiovanni, Gianmarco
8a9ef419-8ff8-48b7-a2f1-5268fc3273a9
Pacini, Clare
aedd6b0b-54c8-49fb-a4ff-df17592ca460
Hall, Zoe
90f578da-ee5a-4a60-bced-b49cc0cbc59c
Dowbaj, Anna M.
bcc5944c-e1c5-42cf-90d0-de20f550ddce
Arnes-Benito, Robert
a15d8267-9570-4411-8ef1-7c4c465bb499
Sljukic, Aleksandra
71f91178-ea05-4ac5-907a-db5a2ee4299c
Prior, Nicole
27851f03-6041-4409-a15c-a2a164b883e0
Kakava, Sofia
8a228b82-013d-4351-8015-8675ea517967
Bradshaw, Charles R.
14ac7ee8-b608-4335-bfb7-2246add5a939
Davies, Susan
6878890f-b27b-411a-9157-b74dca77185f
Vacca, Michele
9e4fa176-34fc-41b4-87b5-ea61a4f36fd8
Saeb-Parsy, Kourosh
598a9eb8-f4b0-45e4-ac27-679cff7d2919
Koo, Bon-Kyoung
df7efb66-cd4e-4e86-8a57-4116130e8fb1
Huch, Meritxell
defdc21f-6ca2-4a97-ab38-436adce9d37c
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).
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.
Text
Accepted_NatComms
- Accepted Manuscript
Text
s41467-021-27923-z
- Version of Record
More information
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
Catalogue record
Date deposited: 03 Feb 2022 17:46
Last modified: 06 Jun 2024 02:08
Export record
Altmetrics
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:
Sofia Kakava
Author:
Charles R. Bradshaw
Author:
Michele Vacca
Author:
Kourosh Saeb-Parsy
Author:
Bon-Kyoung Koo
Author:
Meritxell Huch
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics