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：
8386046
负责人：
DAQING WU
金额：
$ 20.34万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386046
关键词：
Actins Adherens Junction Animal Model Biological Markers Cancer Model 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 mortality novel pre-clinical prevent promoter 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. PUBLIC HEALTH RELEVANCE: EPLIN as a Molecular Target of Genistein In Preventing Prostate Cancer Metastasis Metastasis is the major cause of death from prostate cancer, the most common cancer in men in Western countries. Although several new drugs are currently available for the management of metastatic disease, these therapies can only extend the median survival by approximately 3 months at high cost, which poses a huge burden on patients, their families and the healthcare system. Given the promise of genistein as a safe, efficacious and cost-effective preventive agent that could be implemented before the development of metastasis, it is imperative to understand the molecular mechanism by which genistein inhibits prostate cancer metastasis. Our application will provide mechanistic basis and novel biomarkers for clinical investigation of genistein in the prevention of metastasis at early stages, which could significantly contribute to our efforts of reducing cancer mortality and improving healthcare in the United States and globally.

描述（由申请人提供）：Eplin作为染料木黄酮的分子靶标在预防前列腺癌转移染料木黄酮（一种主要的饮食异黄酮）中，其消耗与前列腺癌（PCA）患者的死亡率降低有关，已成为一种有希望的转移抑制剂。尽管如此，染料木黄酮在阻断癌细胞中转移性级联反应方面的作用机理仍然未知。在此应用中，我们将检验以下假设：诱导eplin是一种关键机制，其中染料木黄酮抑制PCA细胞侵入性的获取并防止肿瘤转移。我们提出了两个具体目标。在AIM 1中，我们将阐明染料木黄酮上调Eplin并抑制PCA细胞中EMT的分子机制。假设是染料木黄酮在转录水平上诱导eplin表达，从而抑制EMT并抑制侵入性表型。我们将通过抑制蜗牛依赖性抑制EPLIN启动子来确定染料木黄酮是否激活Eplin启动子。将检查染料木黄酮对PCA细胞侵袭性的体外作用。这个目标将阐明染料木黄酮在阻断PCA细胞中转移性级联反应中的新型作用机理。在AIM 2中，我们将确定染料木黄酮在上调eplin并预防临床前模型中转移的体内影响。假设是，体内染料木黄酮可以有效地增加eplin的表达，并显着降低动物模型中的转移性发病率。 PCA转移的心脏内模型将用于评估染料木黄酮在体内的疗效上调eplin，抑制EMT并降低转移性发生率。这些研究将提供机械基础和新型生物标志物，用于在早期预防转移中对染料木黄酮进行临床研究，从而显着有助于我们改善PCA患者生存的努力。公共卫生相关性：Eplin作为染料木黄酮在预防前列腺癌转移中的分子靶标是前列腺癌死亡的主要原因，前列腺癌是西方国家男性最常见的癌症。尽管目前有几种新药可用于转移性疾病的管理，但这些疗法只能以高昂的成本将中位生存期扩大了大约3个月，这给患者，家人和医疗保健系统带来了巨大负担。鉴于染料木黄酮作为可以在转移发展之前可以实施的安全，有效和成本效益的预防剂的承诺，因此必须了解染料木黄酮抑制前列腺癌转移的分子机制。我们的应用将提供机械基础和新颖的生物标志物，用于在早期预防转移中对染料木黄酮进行临床研究，这可能会极大地有助于我们降低癌症死亡率和改善美国和全球医疗保健的努力。