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PTH-related peptide and vit D in prostate cancer growth

PTH 相关肽和维生素 D 在前列腺癌生长中的作用

基本信息

批准号：
7813115
负责人：
MIRIAM FALZON
金额：
$ 22.55万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-07 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7813115
关键词：
Adhesions Adverse effects Affinity Basement membrane Biological Assay Bone neoplasms Breast Cancer Cell Growth Cancer Patient Carcinoma Cell Adhesion Cell Proliferation Cell surface Cells Cessation of life Chemopreventive Agent Clinical Trials Collagen Type I Colon Carcinoma Data Development Diagnosis Disease Down-Regulation Elements Extracellular Matrix Extracellular Matrix Proteins Fibronectins Gene Expression Genes Goals Growth Growth Factor Human Immunoprecipitation In Vitro Integrins LNCaP Laboratories Laminin Lead Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Metastatic Neoplasm to the Bone Modeling Molecular Morbidity - disease rate Neoplasm Metastasis Nude Mice Pain Pathway interactions Peptides Play Process Property Prostate Prostate carcinoma Protein Overexpression Publishing Quality of life Research Personnel Risk Factors Role Site Skeleton Therapeutic Therapeutic Agents Time Transcriptional Regulation Transfection United States Vitamin D Vitamin D Analog Vitamin D Deficiency Vitamin D Response Element Vitamin D3 Receptor Vitamins Work Xenograft procedure analog bone cancer cell cancer diagnosis cell growth cell motility combinatorial gene repression human PTH protein in vivo innovation insight male matrigel men migration mortality mouse model novel novel therapeutics overexpression parathyroid hormone-related protein promoter prostate cancer prevention reconstitution research study therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the largest cause of male cancer death in the United States; many prostate cancer patients have metastatic disease at diagnosis. Vitamin D deficiency is a risk factor for prostate cancer, and 1,25-dihydroxyvitarhin D3 (1,250, the hormonally active form of vitamin D) and noncalcemic analogues have shown therapeutic benefits in clinical trials with prostate cancer patients. Prostate cancer cells produce many growth factors, including parathyroid hormone-related protein (formerly peptide, PTHrP). We show that PTHrP overexpression increases prostate cancer cell (a) proliferation; (b) adhesion to the extracellular matrix proteins collagen types I and IV, laminin, and fibronectin; (c) migration onto laminin and collagen type I; (d) invasion of Matrigel, a reconstituted basement membrane; (e) anchorage-independent cell growth; (f) cell surface expression of the pro-invasive integrin a6|34; and (g) xenograft growth in vivo. 1,250 exerts opposite effects on all these parameters, and downregulates PTHrP gene expression. Both PTHrP and integrin 04 expression are required for the anti-proliferative and anti-invasive effects of 1,250, as shown using siRNAs. We thus hypothesize that (a) PTHrP facilitates prostate cancer metastasis by upregulating pro-invasive integrin expression, and (b) the therapeutic benefits of vitamin D are mediated via both downregulatipn of PTHrP gene expression and a direct effect on integrin expression. This project seeks to understand the relationship between PTHrP, vitamin D and integrin a6p4 in prostate cancer cells, by pursuing three Aims. (1) The pathways via which PTHrP and vitamin D regulate integrin a634 expression will be investigated using siRNAs and integrin promoter deletions/transient transfection assays. Since integrin a6(34 increases cancer aggressiveness, we will determine by immunoprecipitation whether vitamin D alters the association of a6 from (34 to 31. (2) The role of PTHrP and integrin (34 in prostate cancer cell growth and bone metastasis, and the effect of concomitant vitamin D treatment, will be studied in vivo using a nude mouse model. (3) The vitamin D response elements via which vitamin D regulates PTHrP gene expression will be identified by PTHrP gene promoter deletions and transient transfection assays. Understanding the relationship between PTHrP, vitamin D, and pro-invasive integrin expression, and the molecular pathways involved, should lead to the development of new combinatorial therapeutic approaches to manage prostate cancer.

描述（由申请人提供）：前列腺癌是美国男性癌症死亡的最大原因；许多前列腺癌患者在诊断时有转移性疾病。维生素D缺乏是前列腺癌的一个危险因素，1,25-二羟基维生素D3（1,250，维生素D的激素活性形式）和非钙化类似物在前列腺癌患者的临床试验中显示出治疗效果。前列腺癌细胞产生多种生长因子，包括甲状旁腺激素相关蛋白（原肽，PTHrP）。我们发现PTHrP过表达增加前列腺癌细胞(a)的增殖；(b)与细胞外基质蛋白I型和IV型胶原、层粘连蛋白和纤维连接蛋白的粘附；(c)迁移到层粘连蛋白和I型胶原；(d)重组基膜Matrigel的侵入；(e)不依赖于锚定的细胞生长；(f)促侵袭性整合素a6|34的细胞表面表达；(g)异种移植物体内生长情况。1250对这些参数的作用相反，下调PTHrP基因的表达。如使用sirna所示，PTHrP和整合素04的表达是1250抗增殖和抗侵袭作用所必需的。因此，我们假设(a) PTHrP通过上调促侵袭性整合素表达促进前列腺癌转移，(b)维生素D的治疗益处是通过下调PTHrP基因表达和直接影响整合素表达来介导的。本项目旨在通过三个目标来了解前列腺癌细胞中PTHrP、维生素D和整合素a6p4之间的关系。(1) PTHrP和维生素D调节整合素a634表达的途径将通过sirna和整合素启动子缺失/瞬时转染试验进行研究。由于整合素a6（34）增加了癌症侵袭性，我们将通过免疫沉淀确定维生素D是否改变了a6从（34）到（31）的关联。(2)采用裸鼠模型，研究PTHrP和整合素（34）在前列腺癌细胞生长和骨转移中的作用，以及维生素D联合治疗的效果。(3)维生素D调控PTHrP基因表达的维生素D应答元件将通过PTHrP基因启动子缺失和瞬时转染试验来鉴定。了解PTHrP、维生素D和前侵袭性整合素表达之间的关系以及所涉及的分子途径，将有助于开发新的组合治疗方法来治疗前列腺癌。