The prostate stem cell is a target of vitamin D chemoprevention

描述（由申请人提供）：循环维生素D水平与前列腺癌风险呈负相关，已经提出补充维生素D以预防前列腺癌。我们最近建立了一种成年前列腺祖细胞/干细胞（PrP/SC）小鼠模型。成体组织特异性干细胞可能是化学预防的重要靶点。我们研究了维生素D的活性代谢物，1,25 -二羟基维生素D3 [1,25(OH)2D3]对PrP/SC的影响。1,25(OH)2D3阻断增殖，诱导细胞周期阻滞，并增加周期蛋白依赖性激酶抑制剂p21和p27的表达。我们的数据表明，1,25(OH)2D3促进PrP/SC的分化。与前分化一致，我们观察到1,25(OH) 2d3处理的PrP/SC中雄激素受体（AR）表达增加。为了确定维生素D受体转录活性的新靶点并评估整体基因表达变化，我们使用1,25(OH) 2d3处理的PrP/SC的RNA探测基因表达阵列。我们发现了一个信号通路，该信号通路对于125 (OH)2D3对PrP/SC的抗增殖作用是必要和充分的，并且是诱导AR所必需的。初步数据还表明，适度的细胞周期阻滞和更深刻的衰老诱导依赖于该通路。该项目将更详细地探讨前列腺干细胞中维生素D信号通路的作用。我们将评估维生素D的调节机制以及该途径如何与AR信号通路相交，我们将确定体外和体内维生素D导致衰老的信号通路，我们将在前列腺癌遗传模型中测试维生素D阻止前列腺肿瘤进展的能力，该模型以p27依赖的方式通过前列腺上皮内瘤变进展。总的来说，这些研究将影响我们对维生素D信号在前列腺干细胞生长停滞、分化和衰老中的作用的理解，以及维生素D在预防前列腺肿瘤进展中的功能作用。

DESCRIPTION (provided by applicant): Circulating vitamin D levels are inversely associated with prostate cancer risk and supplementation with vitamin D for prostate cancer prevention has been proposed. We recently developed a mouse model of adult prostate progenitor/stem cells (PrP/SC). The adult tissue specific stem cell may be an important target for chemoprevention. We have interrogated the effects of the active metabolite of vitamin D, 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3], on the PrP/SC. 1,25(OH)2D3 blocks proliferation, induces cell cycle arrest, and increases expression of cyclin-dependent kinase inhibitors p21 and p27. Our data suggest that 1,25(OH)2D3 promotes differentiation of the PrP/SC. Consistent with prodifferentiation we observe increased androgen receptor (AR) expression in 1,25(OH)2D3-treated PrP/SC. To identify novel targets of vitamin D receptor transcriptional activity and to assess global gene expression changes we probed gene expression arrays with RNA from 1,25(OH)2D3-treated PrP/SC. We identified a signaling pathway that is both necessary and sufficient for 1,25(OH)2D3 antiproliferative actions on the PrP/SC and is required for induction of AR. Preliminary data also demonstrate a moderate cell cycle block and a more profound induction of senescence, which is dependent on this pathway. This project will interrogate the role of this pathway in vitamin D signaling in the prostate stem cell in more detail. We will evaluate the mechanism of regulation by vitamin D and how this pathway intersects with AR signaling, we will determine the signaling pathway leading to senescence in response to vitamin D both in vitro and in vivo, and we will test the ability of vitamin D to block prostate tumor progression in a genetic model of prostate cancer that exhibits progression through prostatic intraepithelial neoplasia in a p27-dependent manner. Overall these studies will impact our understanding of the effects of vitamin D signaling on prostate stem cell growth arrest, differentiation and senescence and the functional roles of vitamin D in the prevention of prostate tumor progression. PUBLIC HEALTH RELEVANCE: Prostate cancer is a significant health problem in the US which is a candidate disease for chemoprevention strategies. This project will dissect the underlying mechanisms of vitamin D-induced changes on the prostate stem cell, a viable target for chemoprevention strategies. This project will further our efforts to develop rationale chemoprevention strategies for prostate cancer.