My primary goal is to develop into an independent investigator in the field of colon-cancer chemoprevention. My long-term research objectives are to elucidate the mechanisms by which ursodeoxycholic acid exerts anticarcinogenic effects with respect to colon cancer. We have demonstrated that supplemental dietary cholic acid promoted the development of azoxymethane-induced rat colonic tumors. In contrast, dietary ursodeoxycholic acid (UDCA) inhibited tumorigenesis and suppressed cholic acid-induced tumor promotion. To examine the mechanisms by which UDCA causes anticarcinogenic effects, preliminary studies in the proposal demonstrated that UDCA inhibited Cox-2 gene expression at both the mRNA and protein levels and decreased Cox-2 immunostaining in stromal cells within the ACF. Furthermore, HCA-7 cells derived from a human colon cancer, demonstrated up-regulation of Cox-2 in response to deoxycholic acid (DCA). DCA is the major metabolite of the primary bile acid cholic acid, and is a potent tumor promoting bile acid. In contrast, UDCA inhibited DCA-induced Cox-2 up-regulation in HCA-7 cells, further supporting our hypothesis that the chemopreventive actions of UDCA involve, at least in part, the ability of UDCA to inhibit Cox-2 expression in colon cancer. HCA-7 cells, therefore, manifest a similar response to UDCA with respect to Cox-2 inhibition as observed in the AOM model. These cells will, therefore, serve as an ideal in vitro model to dissect the molecular events involved in Cox-2 dysregulation in colonic carcinogenesis. They will also allow us to identify potential mechanisms by which UDCA acts to inhibit Cox-2 expression, and thereby suppress tumorigenesis. In our Specific aims we propose to elucidate the signal transduction pathways and regulatory components by which DCA up-regulates Cox-2, while UDCA suppresses this induction. The current project fits well into my long-term research objectives to evaluate the molecular targets of this chemopreventive bile acid. Our findings in this proposal will also likely identify potential blomarkers that we will validate in a future study involving human ACF.
