Prohibitin调控癌组织内源性雄激素合成促进前列腺癌激素抵抗性进展机制研究

项目名称： Prohibitin调控癌组织内源性雄激素合成促进前列腺癌激素抵抗性进展机制研究

项目编号： No.81202035

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 董培

作者单位： 中山大学

项目金额： 23万元

中文摘要： 前列腺癌组织内雄激素及其受体（AR）的异常激活促进前列腺癌去势抵抗性（CRPC）进展。目前研究表明，癌组织内SREBP信号失衡，细胞核内SREBP-SRE结合增加，促进胆固醇合成并转变为雄激素，导致肿瘤进展。我们研究证实，抗增殖蛋白（PHB）通过其启动子上SRE发挥胆固醇敏感活性，在低胆固醇环境中抑制前列腺癌细胞增殖。PHB同时通过调节E2F信号转录，抑制AR介导的激素敏感前列腺癌细胞增殖。据此，我们推测 "PHB通过调节SREBP和E2F信号通路，在CRPC进展中发挥作用"。为了证实这一假说，我们将采用RNAi技术改变前列腺癌细胞的PHB表达，并采用细胞株以及去势移植瘤小鼠模型动态观察CRPC过程中PHB、雄激素、SREBP及E2F信号通路表达的关系，同时检测不同Gleason分级及不同进展时期人前列腺癌组织内PHB表达差异。进一步揭示PHB表达上调促进CRPC进展的发生与发展机制。

中文关键词： 前列腺癌；膀胱癌；抗增殖蛋白；雌激素；耐药性

英文摘要： The synthesis of androgen and reactivation of androgen receptor(AR) are still the important mediators of Castration-Resistant Prostate Cancer(CRPC) progression. Dysregulation of Sterol Response Element-Binding Proteins(SREBP) results in up-regulation of 68-kDa NH3 domain of SREBP, which transports into the nucleus and binds to the sterol response element(SRE) in the promoter of genes involved in fatty acid and cholesterol synthesis. Cholesterol is converted into downstream androgen which promotes tumor progression. .Our study found increased Prohibitin(PHB) level inhibited proliferation of PC-3 cells in cholesterol deprive media through up-regulating SRE expression .PHB also inhibited the transcription of E2F, thus inhibiting androgen-dependent cells proliferation. Based on these, we hypothesize that "PHB plays an important role in the progression of CRPC through regulating SREBP and E2F signal pathways". To conform this hypothesis, we will 1) Transfect PHB or siRNA to up-regulate or down-regulate PHB expression, then observe the effect of PHB level on androgen,AR,SREBP and E2F expression.2) Detect PHB expression in prostate samples with different Gleason stages and different CRPC progress periods. 3) Using androgen-independent LNCaP cells and castration mouse xenograft model, dynamicly observe the relation betw

英文关键词： Prostate cancer；Bladder cancer；Prohibitin；Estrogen；Drug Resistance