RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the\xa0liver lipid metabolic ground-state

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

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.

Highlights

Rnf43/Znrf3del mice exhibited significant hyperplasia and hepatomegaly at 1 week (Fig. 1b), which persisted throughout the course of the study, resembling the hepatocyte-specific Apc mutant mice[16]
To investigate whether part of the lipid alterations observed was due to a cell-autonomous effect of Rnf43/Znrf[3] in hepatocyte lipid metabolism, we studied the impact of deleting both genes in hepatic cells ex vivo
Cancer genomic studies have identified RNF43 and ZNRF3 as WNT pathway genes mutated in liver cancer[21,22,50]

Summary

Introduction

Rnf43/Znrf[3] deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. 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. We describe that specific deletion of RNF43/ZNRF3 in adult hepatocytes results in liver degeneration, steatohepatitis, increased unsaturated lipids and altered liver lipid zonation. Our observations imply that RNF43/ZNRF3 predispose to liver cancer, at least in part, by altering the hepatocyte metabolic ground-state while, in parallel, preventing the tissue from completely regenerating upon damage. Our results are in agreement with our previously published preprint manuscript (Mastrogiovanni et al.23) and the recent publication by Sun et al, published while our manuscript was under revision[24]

Methods

Results

Conclusion