Preventive Role of VDR in Colorectal Carcinogenesis

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DESCRIPTION (provided by applicant): As a major nutrient required for calcium homeostasis and skeletal development, vitamin D is also known to possess pro-differentiation and anti-cell growth activities. The ability of vitamin D to inhibit cancer cell proliferation has long been linked to its potential as a chemopreventive agent. However, despite numerous in vitro studies, in vivo demonstration of the chemopreventive activity of vitamin D in animals remains scarce, and the underlying mechanism remains unclear. Based on the recent observation that 1,25-dihydroxyvitmain D3 induces E-cadherin expression and liganded VDR directly interacts with beta-catenin protein in cultured colon cancer cells, we hypothesize that vitamin D/VDR antagonizes the APC/beta-catenin signaling pathway in vivo to inhibit colorectal carcinogenesis. The main goal of this pilot study is to use a mouse genetic model to test this hypothesis. The genetic model that we will generate is APCmin/+-VDR-/- mice, which are APCmin/+ mice that lack the VDR gene. APCmin/+ mice are a well-established model of human familial adenomatous polyposis coli syndrome and develop intestinal tumors at a few months of age. To test our hypothesis, we will compare the onset, number and size of intestinal polyps in APCmin/+ and APCmin/+-VDR-/- mice under regular diet, high-calcium diet and high-fat diet conditions. We will also carry out histological, immunohistochemical, cellular and molecular analyses of the intestinal polyps from APCmin/+ and APCmin/+-VDR-/- mice. Observations that APCmin/+-VDR-/- mice develop more severe intestinal tumorigenic phenotypes than APCmin/+ mice will strongly support the notion that vitamin D/VDR plays a preventive role in colorectal carcinogenesis in vivo by antagonizing the APC/beta-catenin pathway. Our long-term goal is to understand the molecular mechanism by which vitamin D/VDR protects against colorectal carcinogenesis, and to explore the potentials of low calcemic vitamin D analogs as chemopreventive agents in colon cancer prevention and treatment, and this pilot study will lay down a solid foundation for our long-term studies.