Abstract B43: The Vitamin D receptor and retinoid X receptor-alpha expression related to DNMT levels in a murine model of colitis

Abstract

Abstract Vitamin D3, whose functionality is controlled by signaling through the vitamin D receptor (VDR), plays a regulatory role in inflammation. To properly signal, VDR must heterodimerize with its signaling partner, Retinoid X Receptor (RXRα). When the signaling capability of Vitamin D3 goes awry, this mechanism of inflammation regulation is unchecked and cells are free to proliferate and release inflammatory signaling molecules. Inflammation and dysregulated Vitamin D3 signaling have been implicated in allowing the progression of colitis to cancer, but the mechanism by which this happens is poorly understood. Previous studies in our laboratory revealed that expression of RXRα is decreased in high-grade dysplasia in a mouse model of colon cancer. Whether RXRα or VDR are downregulated in human colitis remains to be clarified. The dextran sodium sulfate (DSS) model is a well-accepted animal model for human colitis, based on its histological similarity to human disease. Addition of azoxymethane (AOM), a carcinogen, is often utilized to encourage colon cancer development in mice with DSS-induced colitis. As a first step, we examined the expression profiles of RXR and VDR in the DSS induced and the DSS/AOM induced mouse models of colitis. To achieve colitis with the DSS model, ten C57BL/6J mice were given 2% DSS for one week followed by a two week recovery period with water and five control mice received only water. This was repeated two times to simulate the remission and relapses evidenced in human colitis. Mice were sacrificed after the third cycle. For the AOM/DSS model, ten C57BL/6J mice were intraperitoneally (IP) injected with 10mg/kg of AOM (control mice were IP with saline) and allowed to recover for one week with water before being given the same DSS model as described above. Mice were killed after one cycle for the acute model or after three cycles for the chronic model. At sacrifice, colons were either swiss-rolled for IHC analysis of VDR, RXRα and PCNA or the mucosal layer was scraped for determination of VDR, RXRα and DNA methyltranferase (DNMT) expression and protein levels. We found that in both mouse colitis protocols VDR protein levels were decreased with altered levels of RXRα protein. In accord with these primary effects, we also found DNMT expression to be altered. We conclude that downregulation of key transcription factors by epigenetic mechanisms could play a role in murine colitis models. We are also investigating whether this find translates to one's risk for colon cancer Citation Information: Cancer Prev Res 2011;4(10 Suppl):B43.