Cyril Sobolewski 1 , Daniel Abegg 2 , Flavien Berthou 1 , Dobrochna Dolicka 1 , Nicolas Calo 1 , Christine Sempoux 3 , Margot Fournier 1 , Christine Maeder 1 , Anne-Sophie Ay 1 , Pierre-Alain Clavien 4 , Bostjan Humar 5 , Jean-François Dufour 6 , Alexander Adibekian 2 , Michelangelo Foti 7 Show Affiliations »
Abstract
OBJECTIVE: Hepatocellular carcinoma (HCC) development occurs with non-alcoholic fatty liver disease (NAFLD) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC. However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD, thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations. DESIGN: The proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD/HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses. RESULTS: A whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD. Alterations of these TSs/ONCs were preserved or even exacerbated in HCC. Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline/methionine-deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration. CONCLUSION: Cellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis. Among those, overexpression of the oncogenic factor S100A11 promotes inflammation/fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
OBJECTIVE: Hepatocellular carcinoma (HCC ) development occurs with non-alcoholic fatty liver disease (NAFLD ) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC . However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD , thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations. DESIGN: The proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD /HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses. RESULTS: A whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD . Alterations of these TSs/ONCs were preserved or even exacerbated in HCC . Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline /methionine -deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration. CONCLUSION: Cellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis . Among those, overexpression of the oncogenic factor S100A11 promotes inflammation /fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Entities: Chemical
Disease
Gene
Species
Keywords:
fatty liver; hepatocellular carcinoma; nonalcoholic steatohepatitis; oncogenes; tumour markers
Mesh： See more »
Substances： See more »
Year: 2020
PMID： 31919231 DOI： 10.1136/gutjnl-2019-319019
Source DB: PubMed Journal: Gut ISSN： 0017-5749 Impact factor: 23.059