Aryl hydrocarbon receptor promotes hepatocellular carcinoma tumorigenesis by targeting intestine‐specific homeobox expression

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.