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Aryl hydrocarbon receptor promotes hepatocellular carcinoma tumorigenesis by targeting intestine‐specific homeobox expression
Author(s) -
Hsu ShihHsien,
Wang LiTing,
Chai CheeYin,
Wu ChiCheng,
Hsi Edward,
Chiou ShyhShin,
Wang ShenNien
Publication year - 2017
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22658
Subject(s) - aryl hydrocarbon receptor , biology , carcinogenesis , oncogene , cancer research , hccs , cell growth , homeobox , cell cycle , cell , hepatocellular carcinoma , microbiology and biotechnology , transcription factor , gene , genetics
The aryl hydrocarbon receptor (AHR), a major chemical sensor, is thought to play a role in various biological contexts, including cell cycle regulation and tumorigenesis. However, its regulatory mechanisms remain unclear. We propose herein a novel mechanism through which AHR promotes tumorigenesis by targeting expression of the oncogene intestine‐specific homeobox ( ISX ) in hepatocellular carcinoma (HCC). Compared to paired tumor‐adjacent tissues and non‐HCC tumors, HCCs exhibited an increased and hierarchical pattern of AHR expression. Patients exhibiting high AHR expression had a significantly shorter survival duration, compared to those with low and medium expression. Functionally, AHR was found to target the newly discovered proto‐oncogene, ISX , resulting in the increased expression of this gene and its downstream targets, CCND1 and E2F1 . Ablation of AHR or ISX in hepatoma cells suppressed cell growth, whereas overexpression promoted cell proliferation and led to enhanced tumorigenic activity in vitro and in vivo . These results provide evidence to support a critical role for the AHR/ISX axis in HCC tumorigenesis and suggest its potential utility as a new therapeutic and prognostic target for HCC.