title: Aryl hydrocarbon receptor promotes hepatocellular carcinoma tumorigenesis by targeting intestine-specific homeobox expression.
abstract: 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.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shih-Hsien
authors.identifier: 0000-0003-2102-0505
authors.initials: SH
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Wang
authors.affiliation: Faculty of Medicine, Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: Department of Business Management, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Edward
authors.initials: E
authors.lastname: Hsi
authors.affiliation: Faculty of Medicine, Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Hematology-Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Shyh-Shin
authors.initials: SS
authors.lastname: Chiou
authors.affiliation: Division of Hepatobiliary Surgery, Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Faculty of Medicine, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Shen-Nien
authors.initials: SN
authors.lastname: Wang
mesh_terms: D000368:Aged; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D000090063:Proto-Oncogene Mas; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D000090063:Proto-Oncogene Mas; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; C111235:AHR protein, human; C579132:Isx protein, human; C000715470:MAS1 protein, human
keywords: aryl hydrocarbon receptor (AHR); hepatocellular carcinoma (HCC); intestine-specific homeobox (ISX)