去势抵抗性前列腺癌发病机制的研究:PRNCR1扮演的角色?

Our previous studies have confirmed that p110β is involved in the progression of CRPC（castration resistant prostate cancer, CRPC） via aberrant activation of AR；Knockdown of long non-coding RNA PRNCR1(prostate cancer non-coding RNA,PRNCR1) attenuated the viability of prostate cancer cells and the transactivation activity of androgen receptor.It's an assumption that: PRNCR1 promote AR activation directly or combine with p110β to promote AR activation and lead to the progression of CRPC?! In this study, first, we plan to detect the expression and translocation of AR and analysis the change of the target gene expression of AR. And we analyze the impact on AR ubiquitination and phosphorylation by regulate the expression level of PRNCR1; Second, we mean to use RNA immuneprecipitation to select the proteins interacted with PRNCR1 and identify if PRNCR1 promote AR activation directly or combine with p110β to promote AR activation; Third, we will construct prostate cancer cells and mouse xenograft models to verify the effect on CRPC produced by PRNCR1 regulate the AR signaling pathways. Futhremore, we intend to collect tissues and serum of patients to obtain the expression profile of PRNCR1and correlated protein in CRPC, the aim is to investgatethe molecular mechnism of PRNCR1lead ing to CRPC. Taken together,the research will do a lot beneficial to disclose the molecular mechanisms in the CRPC，and also possess the profound scientific implication and superb value for clinical application.

我们前期研究证实p110β通过异常激活AR促进去势抵抗性前列腺癌（CRPC）的发生；既往研究发现敲低前列腺癌非编码RNA1（PRNCR1）表达，不仅抑制前列腺癌细胞的增殖，而且抑制AR与雄激素反应元件结合。由此推测： PRNCR1直接作用或与p110β协同作用，异常激活AR，导致CRPC的发生？！本研究拟通过调节PRNCR1表达水平，检测AR表达、转位情况，分析AR下游靶基因表达的变化及对AR泛素化、磷酸化的影响；通过RNA免疫沉淀技术筛选与PRNCR1相互作用的蛋白，明确PRNCR1直接或与p110β结合促进AR转活；构建前列腺癌动物模型，验证PRNCR1调节AR信号对CRPC的影响；收集前列腺癌患者组织及血清样本，获得PRNCR1及相关蛋白作用于CRPC的表达情况，探讨PRNCR1在CRPC发生的作用机制。此研究为CRPC寻找新的分子治疗靶点，具有重要科学意义和临床应用价值。

既往研究发现前列腺癌非编码RNA1（PRNCR1）过表达可导致前列腺癌的发生，促进前列腺癌的增殖、侵袭及AR异常激活；p110β通过异常激活AR促进雄激素非依赖的去势抵抗型前列腺癌（CRPC）的发生。本研究首先通过调节PRNCR1不同表达水平，检测AR的表达情况及前列腺癌的增殖、侵袭情况，证实了PRNCR1在前列腺癌去势抵抗进展中发挥着重要的作用。其次，本研究通过基因芯片技术检测了雄激素依赖前列腺癌细胞LNCaP与雄激素非依赖的去势抵抗性前列腺癌C4-2细胞中差异表达的长链非编码RNA及mRNA，鉴定出了LINC00963参与到前列腺癌去势抵抗进展中。再次，通过基因芯片技术分析了前列腺癌雄激素去势抵抗相关的基因以及LNCaP与C4-2细胞中p53信号通路差异表达基因，为前列腺癌去势抵抗进展的分子机制的探索提供了理论依据。最后，收集前列腺癌患者血清标本，检测PRNCR1及CD51作用于CRPC的表达情况。总之，本课题的顺利实施对阐明PRNCR1在CRPC进展过程中的分子机制奠定理论基础，为CRPC寻找新的分子治疗靶点，具有重要的科学意义和临床应用价值。