S100A11/ANXA2 belongs to a tumour suppressor/oncogene network deregulated early with steatosis and involved in inflammation and hepatocellular carcinoma development.
Animals
Biomarkers, Tumor
/ immunology
Carcinogenesis
/ immunology
Carcinoma, Hepatocellular
/ immunology
Cell Line
Disease Progression
Drug Discovery
Fatty Liver
/ immunology
Gene Expression Profiling
/ methods
Humans
Inflammation
/ metabolism
Liver
/ immunology
Liver Neoplasms
/ immunology
Mice
Obesity
/ immunology
Prognosis
S100 Proteins
/ immunology
fatty liver
hepatocellular carcinoma
nonalcoholic steatohepatitis
oncogenes
tumour markers
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
03
05
2019
revised:
19
12
2019
accepted:
20
12
2019
pubmed:
11
1
2020
medline:
10
4
2021
entrez:
11
1
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 31919231
pii: gutjnl-2019-319019
doi: 10.1136/gutjnl-2019-319019
doi:
Substances chimiques
Biomarkers, Tumor
0
S100 Proteins
0
S100A11 protein, mouse
0
S100A11 protein, human
146909-89-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1841-1854Informations de copyright
© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.