Vitamin D Status and Prostate Cancer

描述(由申请人提供) 几项人群研究表明，较高的膳食钙摄入量与侵袭性前列腺癌的风险增加有关，建议摄入量达到最佳骨骼健康水平。这可能是由于肾脏合成1，25二羟基维生素D(1，25(OH)2D)减少所致，这是一种具有激素活性的维生素D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，并刺激细胞凋亡。其他流行病学研究支持这样的假设，即维生素D储备不足与前列腺癌风险增加有关。体外研究表明，前列腺细胞可以将25-OH D转化为1，25(OH)2D。虽然通过结合人群和细胞研究的数据可以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一现象在前列腺癌预防领域存在显著差距。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)2D通过nVDR激活遗传程序来预防前列腺癌。我们认为，高钙摄入等饮食因素会抑制血清1，25(OH)2D的保护作用，但不会抑制25-OH D水平升高的保护作用。该应用的具体目的是：(1)确定膳食钙与维生素D摄入量之间的关系以及在NMU-雄激素诱导的前列腺癌形成过程中，血清25-OH D和1，25(OH)2D对前列腺癌的保护作用；(2)确定膳食钙和维生素D在雄激素诱导的细胞增殖和凋亡以及对前列腺上皮基因表达的保护模式中的作用；(3)评估nVDR缺失和1α羟基酶过度表达在前列腺特异的IGF-1转基因小鼠中的后果。在我们的研究中，我们将研究逐步致癌(PIN、原位癌、腺癌)，定量相关的血清生物标志物，并评估前列腺组织中维生素D敏感蛋白和基因的表达，以深入了解饮食中的钙和维生素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械基础。

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.