Vitamin D Status and Prostate Cancer

维生素 D 状况与前列腺癌

• 批准号: 7429683
• 负责人: James C. Fleet
• 金额: $ 31.56万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-13 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429683
• 关键词: 25-hydroxyvitamin D; Address; Adenocarcinoma; Adolescence; Androgens; Animals; Apoptosis; Apoptotic; Biological Markers; Bypass; Caco-2 Cells; Calcium; Cancer Etiology; Carcinoma in Situ; Cell Line; Cell Proliferation; Cells; Chemoprotective Agent; Clinical Research; Communities; DNA Microarray Chip; DNA Microarray format; Data; Development; Diet; Dietary Calcium; Dietary Factors; Dietary intake; Dihydroxycholecalciferols; Disputes; Doctor of Philosophy; Elderly; Employee Strikes; Endocrine; Endocrine system; Ensure; Epidemiologic Studies; Epidemiology, Other; Epithelial; Epithelial Cells; Epithelium; Event; Experimental Models; Feedback; Follow-Up Studies; Food; Friends; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Proteins; Genetic Programming; Grant; Growth; Health Professional; Histology; Homeostasis; Human; In Vitro; Insulin-Like Growth Factor I; Intake; Kidney; Knockout Mice; Laboratories; Life; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medical Oncologist; Microarray Analysis; Mixed Function Oxygenases; Molecular; Molecular Profiling; Molecular Target; Mus; Mutagens; Nuclear; Ohio; Osteoporosis prevention; PCNA gene; Pattern; Phase; Population; Population Study; Predisposition; Prevention; Principal Investigator; Proliferating; Prostate; Protective Clothing; Public Health; Publications; Publishing; Rattus; Receptor Signaling; Recommendation; Relative Risks; Reporting; Research; Research Design; Research Personnel; Risk; Rodent; Rodent Model; Role; S-Phase Fraction; Seminal; Serum; Signal Pathway; Signal Transduction; Skeletal system; Staging; Staining method; Stains; Sun Exposure; Sunscreening Agents; Supplementation; Testing; Tissues; Transcript; Transgenic Mice; UV induced; Vitamin D; Vitamin D Nutrition; Vitamin D3 Receptor; Work; base; bone; bone health; calcium metabolism; cancer cell; cancer risk; carcinogenesis; cell growth; cell population study; design; diet and cancer; experience; feeding; in vivo; insight; men; nutrition; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; prevent; prostate cancer prevention; protective effect; research study; response

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.

描述（由申请人提供） 多项人口研究表明，膳食中较高的钙摄入量（达到最佳骨骼健康水平）与侵袭性前列腺癌的风险增加相关。这可能是由于 1,25 二羟基维生素 D (1,25(OH)2 D) 的肾脏合成减少所致，1,25 二羟基维生素 D 是维生素 D 的一种激素活性形式，通过核维生素 D 受体 (nVDR) 发挥作用，抑制前列腺细胞生长，促进前列腺细胞生长。分化，并刺激细胞凋亡。其他流行病学研究支持维生素 D 储存量低与前列腺癌风险增加相关的假设。体外研究表明，前列腺细胞可以将 25-OH D 转化为 1,25(OH)2 D。虽然可以通过结合群体和细胞研究的数据来推断饮食调节维生素 D 代谢水平在预防前列腺癌中的作用，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着差距。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 可通过 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)2 D 的保护作用，但不会抑制升高的 25-OH D 水平。该申请的具体目的是： (1) 建立 NMU 期间 Wistar-Unilever 大鼠膳食钙和维生素 D 摄入量与血清 25-OH D 和 1,25(OH)2D 对前列腺癌的保护作用之间的关系-雄激素诱导的前列腺癌发生，(2) 确定膳食钙和维生素 D 对雄激素诱导的增殖和细胞凋亡以及前列腺上皮基因表达保护模式的作用，以及 (3) 评估以下结果：前列腺特异性 IGF-1 转基因小鼠中 nVDR 缺失和 1α 羟化酶过度表达易患前列腺癌。在我们的研究中，我们将检查逐步致癌作用（PIN、原位癌、腺癌），定量相关血清生物标志物，并评估前列腺组织中维生素 D 敏感蛋白和基因的表达，以深入了解膳食钙和维生素 D 调节前列腺癌发生的机制通过维生素 D 轴。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。

项目成果

Activation of rapid signaling pathways does not contribute to 1 alpha,25-dihydroxyvitamin D3-induced growth inhibition of mouse prostate epithelial progenitor cells.

• DOI: 10.1002/jcb.22206
• 发表时间: 2009-08-01
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Li, Jia;Fleet, James C.;Teegarden, Dorothy
• 通讯作者: Teegarden, Dorothy

Dairy consumption and the prevention of colon cancer: is there more to the story than calcium?

乳制品消费和结肠癌的预防：除了钙之外还有更多的故事吗？

• DOI: 10.1093/ajcn.83.3.527
• 发表时间: 2006
• 期刊: The American journal of clinical nutrition
• 作者: Fleet,JamesC

Constitutive activation of the mitogen-activated protein kinase pathway impairs vitamin D signaling in human prostate epithelial cells.

丝裂原激活蛋白激酶途径的组成性激活会损害人前列腺上皮细胞中的维生素 D 信号传导。

• DOI: 10.1002/jcp.22139
• 发表时间: 2010
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Zhang,Zhentao;Kovalenko,Pavlo;Cui,Min;Desmet,Marsha;Clinton,StevenK;Fleet,JamesC
• 通讯作者: Fleet,JamesC

Renal cell cancer and nuclear receptor levels--biomarkers or functionally relevant?

肾细胞癌和核受体水平——生物标志物还是功能相关？

• DOI: 10.1016/j.juro.2007.07.064
• 发表时间: 2007
• 期刊: The Journal of urology
• 作者: Fleet,JamesC

What have genomic and proteomic approaches told us about vitamin D and cancer?

关于维生素 D 和癌症，基因组学和蛋白质组学方法告诉我们什么？

• DOI: 10.1111/j.1753-4887.2007.tb00340.x
• 发表时间: 2007
• 期刊: Nutrition reviews
• 影响因子: 6.1
• 作者: Fleet,JamesC