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EPLIN as a Molecular Target of Genistein in Preventing Prostate Cancer Metastasis

EPLIN 作为金雀异黄素预防前列腺癌转移的分子靶点

基本信息

批准号：
8507638
负责人：
DAQING WU
金额：
$ 5.56万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-09 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507638
关键词：
Actins Adherens Junction Animal Model Biological Markers Cancer Patient Cause of Death Cells Chronic Disease Clinical Clinical Trials Colorectal Cancer Consumption Country Cytoskeleton Development Diet Disease Down-Regulation Epithelial Experimental Models Family Gene Targeting Genetic Transcription Genistein Head and Neck Squamous Cell Carcinoma Healthcare Healthcare Systems Human In Vitro Incidence Isoflavones Malignant Neoplasms Malignant neoplasm of prostate Mediating Medical Metastatic Prostate Cancer Modeling Molecular Molecular Target Neoplasm Metastasis Neoplasms Oncogenes Patients Pharmaceutical Preparations Phenotype Pre-Clinical Model Prevention Preventive Printing Prostate Proteins PubMed Regulation Reporting Repression Risk Role Signal Transduction Snails Solid Neoplasm Staging Surrogate Endpoint Testing Tumor Suppressor Proteins United States Xenograft Model base cancer cell cost cost effective epithelial to mesenchymal transition improved in vivo inhibitor/antagonist link protein lymph nodes malignant breast neoplasm men metastasis prevention mortality novel pre-clinical prevent promoter prostate cancer cell prostate cancer model soy survivorship tumor

项目摘要

DESCRIPTION (provided by applicant): EPLIN as a Molecular Target of Genistein In Preventing Prostate Cancer Metastasis Genistein, a major dietary isoflavone whose consumption is associated with reduced mortality in prostate cancer (PCa) patients, has emerged as a promising inhibitor of metastasis. Nonetheless, the mechanism of action of genistein in blocking metastatic cascade in cancer cells remains largely unknown. In this application, we will test the hypothesis that the induction of EPLIN is a crucial mechanism wherein genistein inhibits the acquisition of invasiveness by PCa cells and prevents tumor metastasis. We proposed two Specific Aims. In Aim 1, we will elucidate the molecular mechanism by which genistein upregulates EPLIN and inhibits EMT in PCa cells. The hypothesis is that genistein induces EPLIN expression at transcriptional level, thereby inhibiting EMT and suppressing invasive phenotypes. We will determine whether genistein activates EPLIN promoter by inhibiting Snail-dependent repression of EPLIN promoter. The in vitro effects of genistein on the invasiveness of PCa cells will be examined. This Aim will elucidate a novel mechanism of action of genistein in blocking the metastatic cascade in PCa cells. In Aim 2, we will determine the in vivo effects of genistein in upregulating EPLIN and preventing metastasis in pre-clinical models. The hypothesis is that in vivo administration of genistein could effectively increase EPLIN expression and significantly reduce metastatic incidence in animal models. An intracardiac model for PCa metastasis will be used to evaluate the in vivo efficacy of genistein in upregulating EPLIN, inhibiting EMT and reducing metastatic incidence. These studies will provide mechanistic basis and novel biomarkers for clinical investigation of genistein in the prevention of metastasis at early stages, therefore significantly contributing to our efforts of improving survivorship in PCa patients.

描述(申请人提供)：EPLIN作为Genistein预防前列腺癌转移的分子靶标Genistein是一种主要的饮食异黄酮类药物，它的摄入与前列腺癌(PCA)患者的死亡率降低有关，它已经成为一种很有前途的转移抑制药物。尽管如此，金雀异黄素阻止癌细胞转移级联的作用机制在很大程度上仍不清楚。在这一应用中，我们将检验这一假设，即EPLIN的诱导是金雀异黄素抑制前列腺癌细胞获得侵袭力和防止肿瘤转移的关键机制。我们提出了两个具体目标。在目标1中，我们将阐明金雀异黄素上调EPLIN和抑制PCa细胞EMT的分子机制。假设是金雀异黄素在转录水平诱导EPLIN的表达，从而抑制EMT和抑制侵袭性表型。我们将确定金雀异黄素是否通过抑制蜗牛依赖的EPLIN启动子抑制来激活EPLIN启动子。研究金雀异黄素对PCa细胞体外侵袭能力的影响。这一目的将阐明金雀异黄素阻断前列腺癌细胞转移级联反应的新机制。在目标2中，我们将在临床前模型中确定金雀异黄素在上调EPLIN和防止转移方面的体内作用。假设在动物模型中给予染料木素可以有效地增加EPLIN的表达，并显著降低转移发生率。一种心内前列腺癌转移的模型将被用来评估金雀异黄素在体内的疗效。上调EPLIN，抑制EMT，降低转移发生率。这些研究将为金雀异黄素预防早期转移的临床研究提供机制基础和新的生物标志物，从而为我们提高PCa患者的生存率做出重大贡献。