Abstract
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.
Highlights
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is considered as both a complete epigenetic carcinogen and a potent tumor promoter (Murray et al, 2014)
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 aryl hydrocarbon receptor (Ahr)
The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis
Summary
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is considered as both a complete epigenetic carcinogen and a potent tumor promoter (Murray et al, 2014). Using mouse models that express various Ahr alleles, the mouse Ahr has been shown to play a key role in TCDD-induced promotion of liver tumors. 582 | ACTIVATION OF HUMAN AHR PROMOTES HEPATOCARCINOGENESIS formation compared with mice that bear the Ahrb allele with a high binding affinity when exposed to both the initiation event (DEN) and the promotion event (TCDD) (Kennedy et al, 2014). There is only a 58% similarity in the AHR C-terminal transactivation domain between human and mouse receptors, suggesting that AHR may regulate a distinct subset of genes in response to its activation (Flaveny and Perdew, 2009). DNA microarray analysis on TCDD-treated hepatocytes from WT C57BL6/J mice and humanized AHR C57BL6/J mice showed dramatic species differences in AHR-regulated gene induction and repression (Flaveny et al, 2010). It is unclear whether Gadd45b is an AHR responsive gene and if so, whether Gadd45b coactivates AHR and plays a role in the hepatocarcinogenic effect of AHR
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