Constitutive Activation of the Human Aryl Hydrocarbon Receptor in Mice Promotes Hepatocarcinogenesis Independent of Its Coactivator Gadd45b.

Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE

Publication: 1999- : Cary, NC : Oxford University Press
Original Publication: Orlando, FL : Academic Press, c1998-

Antigens, Differentiation/*genetics ; Basic Helix-Loop-Helix Transcription Factors/*metabolism ; Liver Neoplasms, Experimental/*metabolism ; Receptors, Aryl Hydrocarbon/*metabolism; Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Cocarcinogenesis ; Diethylnitrosamine/toxicity ; Female ; Liver Neoplasms, Experimental/chemically induced ; Liver Neoplasms, Experimental/genetics ; Male ; Mice ; Mice, Transgenic ; Polychlorinated Dibenzodioxins/toxicity ; Receptors, Aryl Hydrocarbon/genetics

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared with the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 β (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis.

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R01 DK099232 United States DK NIDDK NIH HHS; R01 ES023438 United States ES NIEHS NIH HHS

0 (AHR protein, human)
0 (Antigens, Differentiation)
0 (Basic Helix-Loop-Helix Transcription Factors)
0 (Gadd45b protein, mouse)
0 (Polychlorinated Dibenzodioxins)
0 (Receptors, Aryl Hydrocarbon)
3IQ78TTX1A (Diethylnitrosamine)

Date Created: 20181023 Date Completed: 20200120 Latest Revision: 20200309

20231215

PMC6358271

10.1093/toxsci/kfy263

30346592