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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：
8854250
负责人：
DAQING WU
金额：
$ 10.38万
依托单位：
AUGUSTA 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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8854250
关键词：
EPLIN Molecular Target Genistein Preventing

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 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.

染料木黄酮是一种主要的膳食异黄酮，食用染料木黄酮可降低转移率和患者死亡风险，它已成为一种有希望的前列腺癌转移抑制剂。尽管如此，染料木素在阻断癌细胞转移级联中的作用机制仍不甚清楚。在这个应用中，我们将验证一个假设，即诱导EPLIN是染料木素抑制PCa细胞获得侵袭性并阻止肿瘤转移的主要机制。我们提出了两个具体目标。在Aim 1中，我们将阐明染料木素在PCa细胞中上调EPLIN和抑制EMT的分子机制。假设染料木素在转录水平诱导EPLIN表达，从而抑制EMT，抑制PCa细胞的侵袭性表型。我们将通过抑制蜗牛依赖的EPLIN启动子抑制来确定染料木素是否激活EPLIN启动子。我们将研究染料木素对前列腺癌细胞EMT和侵袭性的体外影响。本研究旨在阐明染料木素阻断前列腺癌细胞级联转移的新机制。在Aim 2中，我们将在临床前PCa模型中确定染料木素上调EPLIN和预防转移的体内作用。我们的假设是，在动物模型中，给药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。我们将采用TRAMP小鼠和SCID小鼠原位接种PCa细胞两种PCa转移实验模型，来评估染料木素在体内上调EPLIN、抑制EMT和降低转移发生率的作用。这些研究将验证EPLIN是染料木素的主要分子靶点，可用于临床预防前列腺癌转移。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epithelial protein lost in neoplasm (EPLIN): Beyond a tumor suppressor.

肿瘤中丢失的上皮蛋白 (EPLIN)：超越肿瘤抑制因子。

DOI：
10.1016/j.gendis.2017.03.002
发表时间：
2017
期刊：
Genes & diseases
影响因子：
6.8
作者：
Wu,Daqing
通讯作者：
Wu,Daqing

Pomegranate extract inhibits the bone metastatic growth of human prostate cancer cells and enhances the in vivo efficacy of docetaxel chemotherapy.

石榴提取物抑制人前列腺癌细胞的骨转移生长，增强多西紫杉醇化疗的体内疗效。

DOI：
10.1002/pros.22769
发表时间：
2013
期刊：
The Prostate
影响因子：
0
作者：
Wang,Yanru;Zhang,Shumin;Iqbal,Shareen;Chen,Zhengjia;Wang,Xiaojing;Wang,YongqiangA;Liu,David;Bai,Kevin;Ritenour,Chad;Kucuk,Omer;Wu,Daqing
通讯作者：
Wu,Daqing

Mifepristone Has Limited Activity to Enhance the In Vivo Efficacy of Docetaxel and Enzalutamide Against Bone Metastatic and Castration-Resistant Prostate Cancer.

DOI：
10.21873/anticanres.12074
发表时间：
2017-11
期刊：
Anticancer research
影响因子：
2
作者：
Yang Yang-Yang;Xin Li;K. Mamouni;O. Kucuk;Daqing Wu
通讯作者：
Yang Yang-Yang;Xin Li;K. Mamouni;O. Kucuk;Daqing Wu

Inhibition of skeletal growth of human prostate cancer by the combination of docetaxel and BKM1644: an aminobisphosphonate derivative.

多西紫杉醇和 BKM1644（一种氨基二磷酸盐衍生物）的组合可抑制人前列腺癌的骨骼生长。

DOI：
10.18632/oncotarget.8481
发表时间：
2016
期刊：
Oncotarget
影响因子：
0
作者：
Zhang,Shumin;Gera,Lajos;Mamouni,Kenza;Li,Xin;Chen,Zhengjia;Kucuk,Omer;Wu,Daqing
通讯作者：
Wu,Daqing