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

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。 公共卫生相关性：EPLIN作为Genistein预防前列腺癌转移的分子靶点是导致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治疗转移性疾病，但这些疗法只能以高昂的成本将中位生存期延长约3个月，这给患者、他们的家人和医疗系统带来了巨大的负担。由于金雀异黄素有望成为一种安全、有效和经济的预防药物，可以在转移发生之前实施，因此了解金雀异黄素抑制前列腺癌转移的分子机制是非常必要的。我们的应用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，这将为我们在美国和全球降低癌症死亡率和改善医疗保健做出重大贡献。

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.