• Carol J Díaz-Díaz, Sean M Ronnekleiv-Kelly, Manabu Nukaya, Peter G Geiger, Silvia Balbo, Romel Dator, Bryant W Megna, Patrick R Carney, Christopher A Bradfield, and Gregory D Kennedy.
• *Department of Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, WI †Masonic Cancer Center, University of Minnesota, Minneapolis, MN ‡McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI.
• Ann. Surg. 2016 Sep 1; 264 (3): 429-36.

ObjectiveTo determine the role of the aryl hydrocarbon receptor (AHR) in colitis-associated colorectal tumorigenesis.BackgroundColorectal cancer (CRC) is the third most commonly diagnosed cancer in United States. Chronic intestinal inflammation increases the risk for the development of CRC. We investigated the involvement of AHR, a ligand-activated transcriptional regulator, in colitis-associated colorectal tumorigenesis.MethodsWe used a mouse model of colitis-associated colorectal tumorigenesis that employs treatment with azoxymethane and dextran sodium sulfate. We examined the role of AHR using both an Ahr-deletion mouse model (Ahr) and treatment with the AHR pro-agonist indole-3-carbinol (I3C). Incidence, multiplicity, and location of tumors were visually counted. Tumors were defined as neoplasms. Intestinal inflammation was assessed by quantitative PCR for proinflammatory markers and colon length. Data were evaluated and compared using GraphPad Prism software (version 6, La Jolla, CA).ResultsTumor incidence was increased 32% in Ahr null mice and tumor multiplicity was approximately increased 3-fold compared with wild-type mice (2.4 vs 7; P < 0.05). Furthermore, tumor multiplicity was reduced 92% by treatment of I3C in wild-type mice, whereas the suppressor effect of I3C was not observed in Ahr null mice (P < 0.05).ConclusionsWe found that AHR plays a protective role in colitis-associated colorectal tumorigenesis. This conclusion is based on the observations that Ahr null mice showed increased number of colorectal tumors, and mice treated with I3C exhibited fewer tumors. This study supports the use of AHR agonists such as I3C as a chemopreventive therapy for IBD-associated CRC in human patients.

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