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The role of the Mediator complex subunits MED12 and MED15 in the development of androgen-dependent prostate cancer into androgen-independent castration resistant prostate cancer

介体复合物亚基MED12和MED15在雄激素依赖性前列腺癌发展为雄激素非依赖性去势抵抗性前列腺癌中的作用

基本信息

批准号：
268940839
负责人：
Professor Dr. Sven Perner
金额：
--
依托单位：
Institut für Pathologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/268940839?language=en
关键词：
role Mediator complex subunits MED12

项目摘要

Hormone sensitive prostate cancer (PCa) is commonly treated with androgen deprivation therapy (ADT), but most tumors relapse resulting in a castration-resistant prostate cancer (CRPC) with poor prognosis. These tumors regain the ability to progress under androgen deprived conditions through ADT-driven molecular alterations. Activation of androgen receptor (AR) signaling and hyper-activation of alternative signaling pathways bypassing the AR are potential molecular changes in metastatic PCa cells. Gene expression profiling of cancer tissues and cell lines untraveled changes in gene expression pattern during androgen ablation, in which resistant tumor cells exhibit a reactivation of the androgen regulated program. AR activity and other signaling pathways are critically dependent upon interactions with co-regulatory proteins and complexes. The Mediator complex is an important co-activator for a broad range of regulatory transcriptional factors including AR. In previous studies, we reported that the involvement of the Mediator complex subunits MED12 and MED15 in PCa progression to CRPC and their direct implication in TGFß signaling. Based on our data so far, we hypothesize that MED12 and MED15 are directly implicated in the development of androgen-dependent PCa into androgen-independent CRPC. We propose proving this hypothesis by pursuing three specific aims. Firstly, we will investigate whether MED12 and MED15 effect the gene expression changes of androgen dependent prostate cancer cells in response to androgen ablation performing Illumina gene chip analysis. Secondly, we will investigate if MED12 and MED15 influence the ability of androgen dependent PCa cells to survive and proliferate under androgen deprived conditions rendering them resistant to androgen deprivation. Thirdly, we will determine the signaling pathway(s) through which MED12 and MED15 may affect the development of drug resistance in androgen dependent PCa cells. Upon the completion of the above aims, we will have evidence whether MED12 or MED15 may serve as predictive markers for development of drug resistance in PCa. Therefore, our results may lead to recommend the targeting of MED12 or MED15 as this may disrupt key signaling pathways which enable cancer cells to survive during androgen deprivation therapy. Thus, this may call for MED12 or MED15 to be established as therapeutic targets in PCa patients harboring high expression levels of MED12 or MED15.

激素敏感型前列腺癌(PCA)通常采用雄激素剥夺疗法(ADT)治疗，但大多数肿瘤复发导致耐去势前列腺癌(CRPC)，预后差。这些肿瘤通过ADT驱动的分子改变，在雄激素缺乏的条件下重新获得进展的能力。雄激素受体(AR)信号通路的激活和AR旁路替代信号通路的过度激活是转移性PCa细胞潜在的分子变化。肿瘤组织和细胞系的基因表达谱在雄激素消融过程中未发生基因表达模式的变化，在这种变化中，耐药肿瘤细胞表现出雄激素调节程序的重新激活。AR活性和其他信号通路严重依赖于与共调控蛋白和复合体的相互作用。介体复合体是包括AR在内的一系列调控转录因子的重要共同激活因子。在以前的研究中，我们报道了中介复合体亚单位MED12和MED15在PCa进展到CRPC过程中的参与及其在转化生长因子？信号转导中的直接意义。根据我们到目前为止的数据，我们假设MED12和MED15直接参与了雄激素依赖型PCa向雄激素非依赖型CRPC的发展。我们建议通过追求三个具体目标来证明这一假设。首先，我们将利用Illumina基因芯片分析来研究MED12和MED15是否影响雄激素依赖的前列腺癌细胞在雄激素消融反应中基因表达的变化。其次，我们将研究MED12和MED15是否影响雄激素依赖型PCa细胞在雄激素剥夺条件下的生存和增殖能力，从而使其对雄激素剥夺产生抵抗。第三，我们将确定MED12和MED15可能影响雄激素依赖的PCa细胞耐药发展的信号通路(S)。在上述目标完成后，我们将有证据表明MED12或MED15是否可以作为预测PCa耐药的标志物。因此，我们的结果可能会导致建议靶向MED12或MED15，因为这可能会扰乱使癌细胞在雄激素剥夺治疗期间存活的关键信号通路。因此，这可能要求将MED12或MED15确立为拥有MED12或MED15高表达水平的PCa患者的治疗靶点。