lincRNA-ETS1-2上调癌基因ETS-1表达促进雄激素非依赖性前列腺癌演进的机制

The evolution from androgen-dependent prostate cancer to androgen-independent prostate cancer is a key problem for treatment and study of prostate cancer. Whether lncRNA is involved in this process has not been reported. Using microarray to compare the expression files of lncRNA between the androgen-dependent prostate cancer cell LNCaP and androgen-independent LNCaP-AI, a large number of differentially expressed lncRNAs were find out. The preliminary study results displayed that lincRNA-ETS1-2 had a positive-regulation effect on oncogene ETS-1, while the up-regulation of lincRNA-ETS1-2 in LNCaP-AI was associated with the activation of IL-6/JAK/STAT3 signaling pathway. On this basis, our group will explore the mechanism of lincRNA-ETS1-2 up-regulating the expression of oncogene ETS-1 to promote the evolution of androgen-independent prostate cancer, and how the lincRNA-ETS1-2 is activated transcriptionally by IL-6/JAK/STAT3 pathway at the cellular level. Moreover, mouse xenograft model will be constructed to observe that the up-regulation of ETS-1 by lincRNA-ETS1-2 result in raised activity in invasion and metastasis of prostate cancer. Last, clinical specimens of prostate cancer will also be collected to validate the correlation between lincRNA-ETS1-2 and ETS-1 up-regulation. This project can help to unravel the molecular mechanism of the transformation from androgen-dependent prostate cancer to androgen-independent prostate cancer, and provide a theoretical basis for the diagnostic and treatment of the androgen-independent prostate cancer.

前列腺癌由雄激素依赖性演进为非依赖性的转型过程是前列腺癌治疗和研究的难点，lncRNA是否参与这一过程尚未见报道，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-ETS1-2对癌基因ETS-1有正调控作用，而lincRNA-ETS1-2在LNCaP-AI中表达上调，与IL-6/JAK/STAT3信号通路的激活相关。本项目将在此基础上进行以下研究：①在细胞水平研究lincRNA-ETS1-2受IL-6/JAK/STAT3通路转录激活，并上调ETS-1促进前列腺癌转型的机制；②利用小鼠移植瘤模型研究lincRNA-ETS1-2上调ETS-1促进前列腺癌侵袭转移的机制；③收集临床标本验证lincRNA-ETS1-2和ETS-1上调的相关性。为控制前列腺癌的转型提供理论依据。

前列腺癌从激素依赖性向激素非依赖性转型的是前列腺癌基础研究的难点，涉及复杂的分子机制。已有相当数量的研究表明，长链非编码RNA（lncRNA）参与了这一过程，并有可能成为前列腺癌诊断治疗的候选基因和分子标志物。本项目利用lncRNA表达谱芯片，从前列腺癌转型的细胞模型LNCaP和LNCaP-AI筛选出一个新的lncRNA：lincRNA-ETS1-2。在体外和体内进行的功能获得和功能缺失分析显示，lincRNA-ETS1-2促进前列腺癌细胞的增殖、迁移，参与前列腺癌的转型过程，这一功能是通过上调其邻近的癌基因ETS1的表达来介导。RNA核浆分离提取、RNA FISH、报告基因分析以及mRNA半衰期测定的结果显示lincRNA-ETS1-2主要位于胞浆，可能通过增强ETS1mRNA的稳定性在转录后水平上调ETS1的表达，其具体分子机制有待于进一步的深入研究。进一步的研究发现，LNCaP-AI细胞中IL-6/JAK/STAT3信号通路的异常激活，通过lincRNA-ETS1-2启动子3个串联STAT3元件的介导，导致了LNCaP-AI细胞中lincRNA-ETS1-2在转录水平的异常上调。.这一研究的科学意义在于，ETS-1的过表达是前列腺癌转型的关键事件之一，我们阐明了前列腺癌转型中重要的旁路信号途IL-6/JAK/STAT3在转录水平上调lincRNA-ETS1-2，后者对ETS1的转录后调控是ETS-1过表达的一个重要原因。转录因子ETS-1最终转录激活一系列下游靶基因，从而促进肿瘤侵袭、转移，促进CRPC的发生发展。这一研究为全面深入解析前列腺癌转型的分子机制提供了有意义的实验资料。