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Activation of Human Aryl Hydrocarbon Receptor in Promoting Hepatocellular Carcinoma
Author(s) -
Lu Peipei,
Xie Wen
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1189.2
Subject(s) - aryl hydrocarbon receptor , transactivation , hepatocellular carcinoma , tumor promotion , transgene , cancer research , genetically modified mouse , hepatocyte , apoptosis , carcinogenesis , chemistry , biology , endocrinology , medicine , transcription factor , gene , biochemistry , in vitro
Background & Aims TCDD, or dioxin, is a potent liver tumor promoter in rodents through sustained activation of the aryl hydrocarbon receptor (AHR). In addition to the pharmacological model, constitutive activation of AHR by genetic approach has an equal potential in promotion of hepatocellular carcinoma (HCC). However, humans appear to be resistant to most of the adverse health effects of dioxin, and only chloracne is related to serum TCDD levels. This inter‐species difference is largely due to distinct ligand affinity and various gene transactivation selectivity and potential. Here we investigate the liver tumor promoting effect of human AHR and explore the mechanisms underlying its promoting effect. Methods Humanized AHR transgenic mice expressing a constitutively‐activated human AHR (CA‐hAHR) were generated to investigate the direct involvement of human AHR in HCC. A two‐stage initiation‐promotion model of liver tumor was utilized in which a single dose of tumor initiator N‐Nitrosodiethylamine (DEN) was applied at 6 weeks old, followed by AHR activation for 9 months. Results We found that strikingly, constitutively activated human AHR promoted both liver tumor incidence and multiplicity in mice, which was comparable to that in mouse Ahr transgenic mice. This liver tumor promoting effect was associated with increased inflammatory cytokine expression, induced hepatocyte proliferation, as well as enhanced hepatocyte apoptosis. Conclusions Human AHR works at least as efficiently in developing HCC when compared to that in mouse Ahr transgenic mice, suggesting the oncogenic potential of human AHR. Support or Funding Information This work was supported in part by the National Institutes of Health grants DK083952 and HD073070 to Wen Xie.