Preventive Role of VDR in Colorectal Carcinogenesis

描述(申请人提供)：作为钙稳态和骨骼发育所需的主要营养物质，维生素D也具有促进分化和抗细胞生长的活性。长期以来，维生素D抑制癌细胞增殖的能力一直与其作为化学预防药物的潜力有关。然而，尽管有大量的体外研究，但关于维生素D在动物体内的化学预防活性的研究仍然很少，其潜在的机制仍不清楚。根据最近观察到的1，25-二羟基维生素D3诱导结肠癌细胞E-钙粘蛋白表达和连接的VDR与β-连环素蛋白直接相互作用，我们推测维生素D/VDR在体内拮抗APC/β-连环素信号通路，从而抑制结直肠癌的发生。这项初步研究的主要目标是使用小鼠遗传模型来验证这一假设。我们将产生的遗传模型是APCmin/+-VDR-/-小鼠，这是缺乏VDR基因的APCmin/+小鼠。APCmin/+小鼠是人类家族性腺瘤性息肉病结肠综合征的公认模型，并在几个月大时发展为肠道肿瘤。为了验证我们的假设，我们将比较APCmin/+和APCmin/+-VDR-/-小鼠在常规饮食、高钙饮食和高脂肪饮食条件下的肠道息肉的发病情况、数量和大小。我们还将对APCmin/+和APCmin/+-VDR-/-小鼠的肠息肉进行组织学、免疫组织化学、细胞和分子分析。观察到APCmin/+-VDR-/-小鼠比APCmin/+小鼠发展出更严重的肠道肿瘤表型，这将有力地支持这样的观点，即维生素D/VDR通过拮抗APC/β-catenin途径在体内对结直肠癌的发生起到预防作用。我们的长期目标是了解维生素D/VDR预防结直肠癌发生的分子机制，并探索低钙维生素D类似物在结肠癌预防和治疗中的潜力，这一初步研究将为我们的长期研究奠定坚实的基础。

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.