ATF3在前列腺癌雄激素非依赖性形成中的作用研究

前列腺癌(PCa)，尤其是雄激素非依赖性前列腺癌(AIPC)，正在成为威胁我国男性健康的重要疾病。由非正常表达的雄激素受体(AR)调节蛋白引起的AR功能的异常在AIPC形成过程中具有非常重要的作用。我们前期研究结果显示：前列腺癌组织内表达下降的激活转录因子3(ATF3)与AR靶基因PSA的mRNA表达呈显著性负相关；ATF3与AR直接结合并抑制后者的转录活性；PCa细胞向AIPC演变过程中伴有ATF3表达下调。因此，我们推测ATF3可能参与AIPC形成的关键步骤。本项目拟应用分子生物学方法双向调节细胞内ATF3水平，研究ATF3对AR功能的分子调控机制及其在AIPC演变过程中的作用，通过体外细胞功能实验和体内动物实验探索ATF3作为治疗靶点在PCa，特别是在AIPC中的应用价值。本研究对于揭示ATF3在AIPC发展过程中的调控机制和以此为靶点的抗肿瘤药物寻找均具有重要的科学意义和应用价值。

Prostate cancer(PCa), especially the androgen-independent prostate cancer (AIPC) is being the severe life-threatening disease to the men in China. The dysfunction of the androgen receptor (AR) induced by aberrant expression of AR regulators contributes much to the development of the AIPC. We find that activating transcription factor 3 (ATF3),which is down-regulated in prostate cancer tissures, is inversely collelated to the expression of AR-targeted PSA gene in the tested tissues. Futhermore, we demostrate ATF3 works as a novel AR-binding protein and represses AR-mediated transcription activity. Interestingly, ATF3 expression is being down-regulated following the development of androgen-independent prostate cancer in cultrured androgen-dependent prostate cancer cells. Therefore, we propose that ATF3 might play the key role in the development of AIPC. To test the hypothesis, we will overexpress/knock-down the ATF3 using virus system in prostate cancer cells to explore the molecular network of ATF3-AR interaction and its role in the development of AIPC. We will perform in vitro and in vivo strategies to study the role of ATF3 as a novel therapeutic target for the PCa. The significance of the findings will be used to unveil the molecular mechanisms of ATF3 in the development of AIPC, and to provide the potential druggable target defending against prostate cancer, especially for the androgen-indenpent prostate cancer.