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

描述(由申请人提供)：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，它的摄入与患者的转移率和死亡率降低有关，已成为一种很有前途的前列腺癌转移抑制药物。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。在这个应用中，我们将检验这样一个假设，即诱导EPLIN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主要机制。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。假设金雀异黄素在转录水平诱导EPLIN的表达，从而抑制前列腺癌细胞的EMT和侵袭性表型。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EMT和侵袭力的影响。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。在目的2中，我们将确定染料木素在临床前前列腺癌模型中上调EPLIN和防止转移的体内作用。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。采用两种前列腺癌转移的实验模型，即TRAMP小鼠和SCID小鼠原位接种PCa细胞模型，评价染料木黄酮在体内上调EPLIN、抑制EMT和降低转移发生率的作用。这些研究将证实EPLIN是金雀异黄素的主要分子靶点，可用于临床预防前列腺癌转移。

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 decreased rate of metastasis and reduced risk of mortality in patients, has emerged as a promising inhibitor of PCa 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 major 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 in PCa cells. We will determine whether genistein activates EPLIN promoter by inhibiting Snail-dependent repression of EPLIN promoter. The in vitro effects of genistein on EMT and 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 PCa models. The hypothesis is that in vivo administration of genistein could effectively increase EPLIN expression and significantly reduce metastatic incidence in animal models. Two experimental models for PCa metastasis, i.e., TRAMP mice and orthotopic inoculation of PCa cells in SCID mice, will be used to evaluate the in vivo efficacy of genistein in upregulating EPLIN, inhibiting EMT and reducing metastatic incidence. These studies will validate EPLIN as a major molecular target of genistein, which could be exploited clinically for preventing PCa metastasis.