镉通过SENP1调节雄激素受体类泛素化致前列腺癌的分子机制研究

Incidence of prostate cancer is increasing dromaticly in recent years in China. Environmental pollution is one of the important contrubuting factors to the tumor. Cadmium (Cd) is an accumulated environmental pollutant with high toxicity. Cd can act as an endocrine disrupterleading to prostate cancer. Androgen receptor (AR) plays an extremely important role in prostate carcinogenesis.The role of AR depenpends on its transcriptional activity, which can be regulated by post-tranlational SUMOylation. It is reported that SUMO specific protease 1 (SENP1) can deconjugate SUMO from AR and thus increase AR transcriptional activity dramatically.Our previous study showed that cadmium induced SENP1 enhanced AR transcriptional activity by decreasing AR SUMOylation.Interestingly,the induction of SENP1 could be attenuated by ROS mundificant.So we hypothesize that Cd may affect transcriptional activity of AR by regulating SENP1 through ROS associated mechenisms and promote the development of prostate cancer. In this study, we focus on the effect of SENP1 on AR sumoylation to clarify the underlying mechanisms of Cd-induced carcinogenesis in prostate.The results of this research will provide a rationale for the prevention and control strategy for prostate cancer caused by cadmium.

近年来，我国前列腺癌发病率增长极为迅速。环境污染是前列腺癌的重要致病因素。重金属镉是一种持久污染性环境内分泌干扰物，可导致前列腺癌。雄激素受体（AR）在前列腺癌变过程中扮演至关重要的角色。AR作用的发挥依赖于其转录活性，而此活性可被类泛素化修饰调节。研究表明去类泛素化酶SENP1可裂解类泛素与AR之间的共价连接，降低AR的类泛素化水平。我们的前期研究发现镉能够上调SENP1的表达，降低AR的类泛素化修饰水平，增强AR的转录活性。还发现用ROS清除剂处理细胞后，镉对SENP1的上调作用减弱。因此我们推断镉可能通过ROS相关的机制增加SENP1的表达，改变正常的AR类泛素化和去类泛素化稳态，增强AR转录活性，最终促进前列腺癌的发生。本课题拟以AR为切入点，从类泛素化修饰的角度，研究镉致前列腺癌的分子机制，为寻找同类毒物的致癌性风险预测新方法和镉污染所造成疾病的预防控制的新策略提供理论支持。

本研究的目的是通过分析去类泛素化酶SENP1介导的雄激素受体转录活性调节 在镉致前列腺癌中的作用以及镉对 SENP1 基因表达的调控机制，从类泛素化修饰角度阐明镉致前列腺癌的毒理学机制。通过本研究证明了镉可通过增加细胞内ROS水平，进一步激活AKT、ERK、P38、NF-κB信号通路，增强SENP1的表达，促进AR和Nrf2入核，从而导致前列腺癌的发生。此外，我们还探索了另一种可能有内分泌干扰作用的重金属铬的毒性机制，发现铬也可以通过SENP家族分子调节LNCaP细胞中雄激素受体的转录活性，证明内分泌干扰毒性的重金属通过类泛素化修饰调节雄激素受体活性，可能具有普遍性。我们的研究为寻找同类毒物的内分泌干扰毒性和致癌性风险预测新方法提供理论支持。