Vitamin D Status and Prostate Cancer

描述（由申请人提供） 几项人群研究表明，在建议的最佳骨骼健康摄入水平下，较高的膳食钙与侵袭性前列腺癌的风险增加有关。这可能是由于肾脏合成1，25二羟维生素D（1，25（OH）2 D）减少，这是一种维生素D的肾脏活性形式，通过核维生素D受体（nVDR）发挥作用，抑制前列腺细胞生长，促进分化，刺激凋亡。其他流行病学研究支持这一假设，即低维生素D储存与前列腺癌风险增加有关。体外研究表明，前列腺细胞能将25-OH D转化为1，25（OH）2D.虽然可以通过结合来自群体和细胞研究的数据来推断饮食调节维生素D代谢物水平在前列腺癌预防中的作用，但在受控的体内环境中证明这种现象代表了前列腺癌预防领域的显著差距。我们的假设是，高维生素D状态（即高血清25-OH D）和高血清1，25（OH）2 D通过nVDR激活遗传程序来预防前列腺癌。我们认为膳食因素如高钙摄入会抑制血清1，25（OH）2D的保护作用，但不会抑制升高的25-OH D水平。申请的具体目的是：（1）建立饮食钙和维生素D摄入量与血清25-OH D和1，25（OH）2D对Wistar-Unilever大鼠在NMU-雄激素诱导的前列腺癌发生过程中的前列腺癌保护作用之间的关系，（2）确定膳食钙和维生素D对雄激素的作用-诱导前列腺上皮细胞增殖和凋亡以及基因表达的保护模式，和（3）评估nVDR缺失和1 α羟化酶过表达在前列腺特异性IGF-1中的后果。1转基因小鼠易患前列腺癌。在我们的研究中，我们将检查逐步致癌（PIN，原位癌，腺癌），定量相关血清生物标志物，并评估维生素D敏感蛋白和基因在前列腺组织中的表达，以深入了解膳食钙和维生素D通过维生素D轴调节前列腺癌发生的机制。这些数据将为我们提供预防前列腺癌和优化骨骼健康的饮食建议的机制基础。

DESCRIPTION (provided by applicant) Several population studies suggest that higher dietary calcium, at intake levels suggested for optimal bone health, is associated with an increased risk of aggressive prostate cancer. This may be due to reduced renal synthesis of 1,25 dihydroxyvitamin D (1,25(OH)2 D), a hormonally active form of vitamin D that acts through the nuclear vitamin D receptor (nVDR) to suppress prostate cell growth, promote differentiation, and stimulate apoptosis. Other epidemiologic studies support the hypothesis that low vitamin D stores are associated with increased prostate cancer risk. Studies in vitro show that prostate cells can convert 25-OH D into 1,25(OH)2 D. While a role for dietary modulation of vitamin D metabolite levels in prostate cancer prevention can be inferred by combining data from population and cell studies, demonstration of this phenomenon in a controlled, in vivo setting represents a significant gap in the field of prostate cancer prevention. Our hypothesis is that high vitamin D status (i.e. high serum 25-OH D) and high serum 1,25(OH)2 D protect against prostate cancer by activating genetic programs through the nVDR. We believe that dietary factors like high calcium intake will suppress the protective effect of serum 1,25(OH)2 D but not of elevated 25-OH D levels. The specific aims of the application are to: (1) Establish the relationship between dietary calcium and vitamin D intake and the protective role of serum 25-OH D and 1,25(OH)2D against prostate cancer in Wistar-Unilever rats during NMU-androgen-induced prostate carcinogenesis, (2) Establish the role of dietary calcium and vitamin D on androgen-induced proliferation and apoptosis and on protective patterns of gene expression in the prostate epithelium, and (3) Evaluate the consequence of nVDR deletion and 1alpha hydroxylase over-expression in prostate-specific IGF-1 transgenic mice predisposed to prostate carcinogenesis. In our studies we will examine stepwise carcinogenesis (PIN, carcinoma in situ, adenocarcinoma), quantitate relevant serum biomarkers, and assess expression of vitamin D sensitive proteins and genes in prostate tissue to provide insight into mechanisms whereby dietary calcium and vitamin D modulate prostate carcinogenesis through the vitamin D axis. These data will provide us with the mechanistic basis for dietary recommendations to prevent prostate cancer and optimize bone health.