Trans-acting non-synonymous variant of FOXA1 predisposes to hepatocellular carcinoma through modulating FOXA1-ERα transcriptional program and may have undergone natural selection.
Adult
Asian People
/ genetics
Carcinoma, Hepatocellular
/ genetics
Carrier State
/ pathology
Case-Control Studies
Estrogen Receptor alpha
/ genetics
Female
Gene Expression Regulation, Neoplastic
Gene Frequency
Gene Regulatory Networks
Genetic Predisposition to Disease
Hep G2 Cells
Hepatitis B virus
/ isolation & purification
Hepatocyte Nuclear Factor 3-alpha
/ genetics
Humans
Liver
/ pathology
Liver Neoplasms
/ genetics
Male
Middle Aged
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
/ genetics
Selection, Genetic
Sex Factors
Tissue Array Analysis
Transcription, Genetic
Journal
Carcinogenesis
ISSN: 1460-2180
Titre abrégé: Carcinogenesis
Pays: England
ID NLM: 8008055
Informations de publication
Date de publication:
22 04 2020
22 04 2020
Historique:
received:
24
01
2019
revised:
26
06
2019
accepted:
30
07
2019
pubmed:
11
8
2019
medline:
1
9
2020
entrez:
11
8
2019
Statut:
ppublish
Résumé
Interplay of pioneer transcription factor forkhead box A1 (FOXA1) and estrogen receptor has been implicated in sexual dimorphism in hepatocellular carcinoma (HCC), but etiological relevance of its polymorphism was unknown. In the case control study (1152 patients versus1242 controls), we observed significant increase in HCC susceptibility in hepatitis B virus carriers associated with a non-synonymous Thr83Ala variant of FOXA1 (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.11-1.48, for Ala83-containing genotype, after validation in an independent population with 933 patients versus 1030 controls), a tightly linked (CGC)5/6or7 repeat polymorphism at its promoter (OR 1.32; 95% CI 1.10-1.60, for (CGC)6or7-repeat-containing genotype), and their combined haplotype (OR 1.50; 95% CI 1.24-1.81, for (CGC)6or7-Ala83 haplotype). The susceptible FOXA1-Ala83 impairs its interaction with ERα, attenuates transactivation toward some of their dual target genes, such as type 1 iodothyronine deiodinase, UDP glucuronosyltransferase 2 family, polypeptide B17 and sodium/taurocholate cotransporting polypeptide, but correlates with strengthened cellular expression of α-fetoprotein (AFP) and elevated AFP serum concentration in HCC patients (n = 1096). The susceptible FOXA1 cis-variant with (CGC)6or7 repeat strengthens the binding to transcription factor early growth response 1 and enhances promoter activity and gene expression. Evolutionary population genetics analyses with public datasets reveal significant population differentiation and unique haplotype structure of the derived protective FOXA1-Thr83 and suggest that it may have undergone positive natural selection in Chinese population. These findings epidemiologically highlight the functional significance of FOXA1-ERα transcriptional program and regulatory network in liver cancer development.
Identifiants
pubmed: 31400761
pii: 5546009
doi: 10.1093/carcin/bgz136
doi:
Substances chimiques
ESR1 protein, human
0
Estrogen Receptor alpha
0
FOXA1 protein, human
0
Hepatocyte Nuclear Factor 3-alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
146-158Informations de copyright
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.