去势抵抗性前列腺癌（CRPC）是前列腺癌的治疗难点，发生机制不明，患者预后差。申请合作双方长期致力于CRPC发生机制的研究,并分别揭示了ERG、FOXA1、EZH2和TXNDC5基因在CRPC发生中的作用和机制。最近我们发现某些长链非编码RNA(lncRNA)，如HOTAIR可促进CRPC的发生，提示lncRNA 和CRPC的相关性。本合作课题拟通过RNA-seq平台，整合多种生物信息学技术，系统筛选中国CRPC患者中特异性表达的lncRNA。我们拟分析候选lncRNA在前列腺癌患者中的临床病理学意义及预后价值；体内外实验观察lncRNA在CRPC发生发展中的生物学功能及与雄激素-AR通路的关系；识别lncRNA可能调控的下游靶基因或作用蛋白；整合并建立CRPC中lncRNA的“个性化”调控网络。探讨其作为肿瘤标志物和临床治疗靶点的潜在应用价值，为建立国人个体化的CRPC诊疗方案提供依据。

Castration-resistant prostate cancer (CRPC) has poor prognosis and remains a significant clinical challenge. The molecular mechanisms underlying CRPC remain unclear. The co-applicants are dedicated to the investigation of the mechanisms of CRPC. Our research groups have characterized the roles of several critical genes, including ERG, FOXA1, EZH2 and TXNDC5, in CRPC. Recently, long non-coding RNAs (lncRNAs) are emerging as critical regulators of gene expression and cancer-specific lncRNAs are being rapidly cataloged. Our preliminary studies found that some lncRNAs, for example HOTAIR, plays important roles in driving CRPC progression. And yet, the expression and function of lncRNA in CRPC remain largely unknown. In the current proposal, integrating RNA-seq with sophisticated bioinformatics analysis, we aim to systematically screen for lncRNAs specific to the Chinese CRPC patients. Our project is intended to: 1) characterize the clinico-pathological features and prognostic significance of selected lncRNAs in PCa; 2) determine the biological functions of selected lncRNAs in CRPC; 3) systematically analyze the potential targeted genes and interacting proteins of selected lncRNAs and determine their interaction with key signaling pathways of CRPC, such as those mediated by AR, EZH2, and TMPRSS-ERG gene fusions; 4) establish individualized regulatory network of specific lncRNAs in CRPC. The final goal of our study is to evaluate the potential of candidate lncRNAs as tumor markers and/or therapeutic targets of CRPC and to provide credible evidence for management and individualized treatment rational for Chinese CRPC patients.

去势抵抗性前列腺癌（CRPC）是前列腺癌的治疗难点，发生机制不明，患者预后差。申请合作双方长期致力于CRPC发生机制的研究,并分别揭示了ERG、FOXA1、EZH2和TXNDC5基因在CRPC发生中的作用和机制。最近我们发现某些长链非编码RNA(lncRNA)，如HOTAIR可促进CRPC的发生，提示lncRNA 和CRPC的相关性。我们以雄激素依赖的前列腺癌细胞株LNCaP和非依赖的LNCaP-AI为对象，利用芯片比较二者的lncRNA表达谱，发现大量差异表达的lncRNA,并初步发现lincRNA-PADI2/1对肽基精氨酸脱亚胺酶2（PADI2）的表达有正调控作用。PADI2参与慢性炎症性疾病和肿瘤等病变过程。本课题发现PADI2介导的瓜氨酸化促进去势抵抗性前列腺癌的发生和发展。PADI2是雄激素抑制性基因，在CRPC组织中的表达量明显升高。PADI2与前列腺癌细胞的存活和细胞周期进展有关，体内外实验证实在雄激素剥夺或去势条件下，PADI2可促进癌细胞的增殖。胞浆中的PADI2可保护AR蛋白免于蛋白酶体介导的降解，并促进AR蛋白的入核；入核后通过瓜氨酸化修饰H3R26调控AR对其下游靶基因的表达调控。而PADI2突变体（D180A）无法影响AR蛋白稳定性、入核或转录调控活性。上述效应都依赖于PADI2的瓜氨酸化修饰酶的活性。体内实验还证实联合PADI2抑制剂和AR抑制剂恩杂鲁胺可协同抑制CRPC的发生和进展。通过本课题，发现PADI2通过AR信号通路促进前列腺癌进展，特别是CRPC的发生，提示可将PADI2作为治疗靶点用于治疗前列腺癌。