PCA3及其基因多态性在前列腺癌发生发展中的功能和机理研究

In the field of prostate cancer treatment, there is no effective option for castration-resistant prostate cancer, which has mainly contributed to the mortality of the disease. Accumulative evidences have shown that prostate cancer gene 3(PCA3) is a kind of long non-coding RNA which is specific overexpression in prostate cancer. Currently, PCA3 is used for early diagnosis of prostate cancer. However, the studies on its role in prostate cancer tumorigenesis and development are rare. In pilot experiments, we used siRNA to inhibit the expression of PCA3 in prostate cancer, and found that the proliferation and colony formation functions of prostate cancer cells are significantly inhibited. In addition, we found that PCA3 can be combined with androgen receptor (AR) by EMSA experiment. Therefore, we put forward a new hypothesis that PCA3 may assist AR to enhance AR signal pathway， thereby regulating the expression of downstream target genes and then mediating the development of prostate cancer. Simultaneously, we will study whether PCA3 polymorphism affect the relationship between PCA3 and AR. We will use RIP, RNA pull down, deletion mapping, lentiviruse-based inducible systems, ChIP technology and so on to explore the role of PCA3 in prostate tumorigenesis and progression, elucidate the molecular mechanism of PCA3 in tumorigenesis and progression of prostate cancer. This study will originally reveal a new mechanism of prostate cancer tumorigenesis and development from lncRNA angle, and provide new therapeutic targets for prostate cancer.

前列腺癌发生去势抵抗性进展是前列腺癌治疗的难点，亦是其死亡的主要原因。前列腺癌抗原3(PCA3)是一种在前列腺癌中特异性高表达的长链非编码RNA。目前，PCA3被用于前列腺癌的早期诊断，其在前列腺癌中的作用还少见研究。本研究前期利用siRNA干扰PCA3后，前列腺癌细胞生长受到明显抑制。此外，通过EMSA实验还发现PCA3可与雄激素受体（AR）结合。因此，本项目提出PCA3可能通过协助AR增强AR信号通路，进而调节下游靶基因的表达，实现调控前列腺癌发生发展的假说。同时，我们还将研究PCA3多态性是否影响PCA3与AR的关系。为此，我们将采用RIP和RNA pull down、缺失作图、腺病毒载体转染、RNA干扰、ChIP等手段，从分子、细胞及组织水平多方面探讨PCA3在前列腺癌发生发展中的作用机制。本项目将从长链非编码RNA角度揭示前列腺癌发生发展的新机制，为前列腺癌的治疗提供新靶点。

前列腺癌发生去势抵抗性进展是前列腺治疗的难点和死亡的主要原因。阐明前列腺癌进展至去势抵抗性的分子机制为寻找有效的特异性高的治疗靶点提供了突破口。本项目从lncRNA的角度揭示了前列腺癌发生发展的新机制。通过RNA pull down、缺失作图、基因敲除改造等手段，本课题发现PCA3干扰后前列腺癌细胞生长受到明显抑制，同时发现PCA3能特异性地结合AR并协助增强AR下游分子的表达从而调控前列腺癌细胞的生长。在临床样本中也进一步验证了PCA3、AR和AR下游分子之间的关系。该研究为寻找前列腺癌新的有效的治疗靶点提供了新的机制学说。