我国每年有2.66万人死于前列腺癌，在泌尿系统肿瘤中死亡率排名第一位, 去势抵抗是导致前列腺癌患者死亡的最核心原因之一，且目前对这一机制研究尚缺乏突破性的进展。项目组前期研究中发现，RNA剪切功能相关蛋白USP39在去势抵抗前列腺癌CRPC中表达显著升高，前列腺特异性表达USP39的转基因鼠可自发形成类前列腺癌样改变，同时USP39直接调控雄激素受体剪切异构体7（AR-V7）的过度表达，而AR-V7是介导CRPC雄激素通路持续激活的重要原因。项目组拟从大量CRPC临床标本及病例出发，明确USP39表达与CRPC发生及转归的相关性；从分子及细胞水平阐明USP39调控AR-V7表达及可变剪切的分子机制及相关的肿瘤学功能；最后通过动物在体实验进一步验证USP39调控AR-V7形成及对CRPC发生影响；以此揭示USP39介导CRPC发生的关键作用机制，为CRPC的治疗提供新的理论依据及药物靶点。

In our country, 26,600 patients each year died of prostate cancer whose mortality rate is highest in urological malignancy，with castration resistance being the most core cause of death of prostate cancer. However, the current study on this mechanism is still lack of any breakthrough yet. Based on our previous research，one gene named as USP39 could be over expressed in the castration-resistant prostate cancer and USP39 transgenic mice could spontaneously form prostate cancer-like changes. In the meantime, USP39 directly lead to the overexpression of the androgen receptor cleavage isomers 7 (AR-V7), which was a significant cause of persistent activation of CRPC androgen pathway. Built on a large number of CRPC clinical specimens and cases，we investigated the correlation between the expression of USP39 and the occurrence and prognosis of CRPC. The molecular mechanism of the regulation effect of USP39 on the AR-V7 formation，variable shear and relevant oncological effects was clarified on molecular and cellular level. Finally, we did vivo experiments to make more explicit on the regulation effect of USP39 on the formation of AR-V7 and its effect on CRPC, which revealed the core mechanism of USP39-mediated CRPC，providing novel theoretical basis and potential drug targets for CRPC treatment.