Objective To determine the role of the aryl hydrocarbon receptor (AHR) in colitis-associated colorectal tumorigenesis. Summary Background Data Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in United States. Chronic intestinal inflammation increases the risk for the development of CRC. We questioned the involvement of AHR, a transcriptional regulator for intestinal innate immunity and inflammation, in the colitis-associated tumorigenesis. Methods We used a mouse model for chemically-induced colorectal tumorigenesis by treatment of azoxymethane (AOM) and sodium dextran sulfate (DSS). We examined the role of AHR using Ahr-deletion mouse model and I3C treatment. Tumor incidence, number and location were visually counted. Tumor multiplicities were evaluated and compared using GraphPad Prism software (version 6, LaJolla, CA). Results In Ahr null mice, the tumor incidence was 32% increased and the mean tumor number was approximately 3 time increased compared to WT mice (7 v 2.4, P<0.05). The tumor number was 92% decreased by treatment of I3C in WT mice, while the chemopreventive effect of I3C was not observed in Ahr null mice (P<0.05). Conclusions We found that the AHR may play a protective role in colitis-associated colorectal tumorigenesis. This work supports the application of AHR agonists such as I3C as a chemopreventive therapy for CRC in human patient.
The polyphenolic flavone chrysin has been evaluated as a natural chemopreventive agent due to its anti-cancer effects in a variety of cancer cell lines. However, the mechanism of the chemopreventive effect has been not well established, especially in human colorectal cancer cells. We evaluated the chemopreventive effect of chrysin in three different human colorectal cancer cell lines. We found that chrysin treatment consequently reduced cell viability via induction of apoptosis. We identified that the involvement of up-regulation of pro-apoptotic cytokines tumor necrosis factor (Tnf) α and β genes and consequent activation of the TNF-mediated transcriptional pathway in chrysin-induced apoptosis. Using our generated AHR siRNA expressing colorectal cancer cells, we demonstrated that the chrysin-induced up-regulation of Tnfα and β gene expression was dependent on the aryl hydrocarbon receptor (AHR), which is a ligand-receptor for chrysin. Subsequently, we found that the AHR siRNA expressing colorectal cancer cells were resistant to chrysin-induced apoptosis. Therefore, we concluded that AHR is required for the chrysin-induced apoptosis and the up-regulation of Tnfα and β gene expression in human colorectal cancer cells.
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