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

描述（由申请人提供）：EPLIN作为染料木黄酮的分子靶点预防前列腺癌转移染料木黄酮是一种主要的膳食补充剂，其消耗与前列腺癌（PCa）患者的死亡率降低相关，已成为一种有前景的转移抑制剂。然而，染料木黄酮在阻断癌细胞中的转移级联中的作用机制在很大程度上仍然未知。在本申请中，我们将测试EPLIN的诱导是其中染料木黄酮抑制PCa细胞获得侵袭性并防止肿瘤转移的关键机制的假设。我们提出了两个具体目标。目的1：阐明染料木黄酮上调前列腺癌细胞EPLIN和抑制EMT的分子机制。假设染料木黄酮在转录水平诱导EPLIN表达，从而抑制EMT并抑制侵袭表型。我们将确定染料木黄酮是否通过抑制EPLIN启动子的Snail依赖性阻遏来激活EPLIN启动子。将检查染料木黄酮对PCa细胞侵袭力的体外作用。这一目的将阐明染料木黄酮在阻断PCa细胞中的转移级联中的新的作用机制。在目标2中，我们将确定金雀异黄素在临床前模型中上调EPLIN和预防转移的体内作用。假设在动物模型中，染料木黄酮的体内给药可以有效地增加EPLIN表达并显著降低转移发生率。将使用PCa转移的心内模型来评估染料木黄酮在PCa转移中的体内功效。 上调EPLIN、抑制EMT和降低转移发生率。这些研究将为染料木黄酮预防前列腺癌早期转移的临床研究提供机制基础和新的生物标志物，从而为我们提高前列腺癌患者的生存率做出重要贡献。 公共卫生相关性：EPLIN作为Genistein的分子靶点在预防前列腺癌转移中的作用转移是前列腺癌死亡的主要原因，前列腺癌是西方国家男性中最常见的癌症。虽然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延长约3个月，这对患者，他们的家庭和医疗保健系统造成了巨大的负担。鉴于染料木黄酮作为一种安全，有效和具有成本效益的预防剂，可以在转移的发展之前实施的承诺，这是必要的，以了解染料木黄酮抑制前列腺癌转移的分子机制。我们的申请将为染料木黄酮在早期阶段预防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的努力做出重大贡献。

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.