A Constitutively Active Dioxin/Aryl Hydrocarbon Receptor Promotes Hepatocarcinogenesis in Mice

Abstract

The dioxin/aryl hydrocarbon receptor (AhR) functions as a ligandactivated transcription factor regulating transcription of a battery of genes encoding enzymes involved in drug metabolism. Known ligands include polycyclic aromatic hydrocarbons, certain polychlorinated biphenyls, and the polyhalogenated dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin. Both polyhalogenated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin are potent promoters of rodent hepatocarcinogenesis in two-stage initiation-promotion experiments. Although several lines of evidence indicate the involvement of the AhR in toxic effects mediated by polyhalogenated biphenyls and dioxins, its involvement in tumor promotion has not been unequivocally proven. In the present study, a transgenic mouse line expressing a constitutively active AhR (CA-AhR) has been used to investigate the role of the AhR in hepatocarcinogenesis. Male AhR wild-type and CA-AhR-transgenic B6C3F1-mice were treated with a single injection of the hepatocarcinogen N-nitrosodiethylamine at 6 weeks of age and were subsequently kept untreated on control diet. Thirty five weeks after carcinogen treatment, mice were sacrificed, and the prevalence and multiplicity of liver tumors were determined. Whereas only 1 small liver tumor was observed in 15 AhR-wild-type mice, 19 tumors (two >1 cm in diameter) were present in 18 CA-AhR-transgenic mice. This result demonstrates the oncogenic potential of the activated AhR and implicates an important role of the receptor in promotion of hepatocarcinogenesis. A microarray-based gene expression-profiling analysis revealed down-regulation in the liver of CA-AhR-transgenic mice of a cluster of genes encoding heat shock proteins, including GRP78/BiP, Herp1, Hsp90, DnaJ (Hsp40) homologue B1, and Hsp105, which are important for protein folding and quality control.

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

“…AHR activation promotes clonogenicity and invasiveness of cancer cells 11,17 . Transgenic mice with a constitutively active AHR spontaneously develop tumours 18,19 , and the repressor of the AHR (AHRR) represents a tumour suppressor in multiple human cancers 20 . The aberrant phenotype of Ahr-deficient mice points to the existence of endogenous AHR ligands 21 .…”

Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis

“…Both AHR-negative mouse hepatoma Hepa1c1c7 cell variants [Ma and Whitlock, 1996], and human HepG2 hepatoma cells transfected with AHR siRNA [Abdelrahim et al, 2003] show a slower progression through the cell cycle, attributed to a delay in the transition from G 1 to S. These results suggest that the AHR plays an endogenous role in the promotion of cell cycle progression and that this role is independent of activation by exogenous ligands. This conclusion is significantly strengthened by the findings that, in the absence of ligand, expression of a constitutively active AHR variant in transgenic mice causes pro-proliferative effects, such as induction of stomach tumors [Andersson et al, 2002], and promotion of hepatocarcinogenesis [Moennikes et al, 2004]. Paradoxically, expression of the same variant AHR in human Jurkat cells causes growth inhibition and apoptosis [Ito et al, 2004].…”

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

“…In addition, the AhR repressor (AhRR) and miRNAs posttranscriptionally targeting AhR are predominantly suppressed in cancer (20)(21)(22). Direct evidence showing that AhR is an oncogenic driver gene was demonstrated by the finding that transgenic mice with constitutively activated AhR (AhR CA) developed gastric cancer and hepatocellular carcinoma (23,24). Although there is no direct evidence showing that the activation of AhR leads to NSCLC tumorigenesis, AhR has attracted increasing attention in this type of cancer.…”