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) 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。

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

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

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