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Evaluating the Role of VDR Polymorphisms and Beta-catenin Signaling in Colorectal Neoplasia

出版	University of Arizona, 2009
URL	http://books.google.com.hk/books?id=Ep7ZjwEACAAJ&hl=&source=gbs_api

註釋Colorectal cancer is estimated to cause approximately 50,000 deaths each year in the United States. Epidemiological studies have demonstrated an inverse association between sunlight exposure, which stimulates the formation of vitamin D in the skin, and colorectal carcinoma. Laboratory studies report that metabolites of vitamin D, acting through the vitamin D receptor (VDR), regulate cellular proliferation, differentiation and apoptosis. In addition, VDRcontains a polymorphic variant, FokI, which results in two different isoforms of VDR. We have demonstrated a differential suppression of & beta;-catenin transcriptional activity by these isoforms in the presence of 1,25(OH)2D3(1,25D). Epidemiological evaluation of metachronous colorectal adenoma formation indicates thatVDRincludes several single nucleotide polymorphisms (SNPs) which influence the odds of developing colorectal adenoma. In addition, we have found full length Adenomatous Polyposis Coli (APC), a frequently mutated tumor suppressor gene in colorectal cancer, augments both the interaction of VDR and & beta;-catenin as well as the suppression of & beta;-catenin transcriptional activity in the presence of 1,25D. We have also demonstrated in epidemiological studies that the presence of a T-A haplotype inAPCcodons 486 and 1822, respectively, reduces the odds of any metachronous adenoma by 27% [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.59 - 0.91]. Taken together, these data support not only a protective role for vitamin D acting through the VDR, but also for an important role of heritable polymorphic variation inVDRandAPCin carcinogenesis.