lincRNA-BCSCA1募集PRC2调控膀胱肿瘤干细胞自我更新的机制研究

Emerging evidence shows cancer stem cells are the main reason of therapy resistance, but the mechanism is not well understood. The deregulation of long intergenic noncoding RNA(lincRNAs) can play an important role in cancer, acting as oncogenes or tumor suppressor genes. Moreover, lincRNAs play significant regulatory roles in the self-renewal of normal stem cell. However, the roles of lincRNAs in cancer stem cell are remain largely unknown. Our previous study found that lincRNA-BCSCA1 is increased in expression in bladder CSCs. Overexpression or knockdown of lincRNA-BCSCA1 significantly enhanced or inhibited the self-renewal and proliferation of bladder CSCs in vitro and vivo. Furthermore, we identified that lincRNA-BCSCA1 binds EZH2, a critical domain of PRC2, by co-immunoprecipitation. Therefore, we suppose a new mechanism that lincRNA-BCSCA1 induces PRC2 to regulate a serial stem cells related gene epxression to maintain the self-renewal of bladder CSCs, leading to cancer therapy resistance and relapse. To gain the proof of lincRNA-BCSCA1 regulate self-renewal of bladder CSCs by PRC2, we will perform co-immunoprecipitation, microarray and sequencing-based methylation analysis. This study is aim to elucidate the function and mechanism of lincRNA-BCSCA1 in bladder CSCs and how they modulate the target genes by recruiting PRC2, in order to identify the new targets for bladder cancer stem cell targeting therapy and the clinical significance of lincRNA-BCSCA1 in bladder cancer relapse, therapy resistance and prognosis.

肿瘤干细胞(Cancer Stem Cells,CSCs)存在是治疗失败的主要原因，但机制未明，长链基因间非编码RNA(lincRNA)在肿瘤细胞和正常干细胞中的关键调控作用提示lincRNA可能对CSCs也起着重要的调控作用。我们预实验发现lincRNA-BCSCA1在膀胱CSCs中高表达，上下调BCSCA1后，膀胱CSCs的干性相应地明显增加或减弱。进一步免疫共沉淀证明BCSCA1和PRC2的EZH2结合，由此我们提出BCSCA1调控膀胱CSCs干性新机制：BCSCA1通过募集组蛋白修饰复合物PRC2，调控一系列干性因子表达，从而维持膀胱CSC干性，导致肿瘤复发、耐药。本研究拟进一步采用免疫共沉淀、基因芯片和甲基化测序等技术，获得BCSCA1通过PRC2调控膀胱CSCs自我更新的可靠证据，为发现膀胱癌治疗新靶点提供科学依据，确定BCSCA1在膀胱癌复发、耐药和预后中的意义，指导临床实践

肿瘤干细胞(Cancer Stem Cells,CSCs)存在是膀胱癌治疗失败的主要原因，但机制未明，长链基因间非编码RNA(lincRNA)在肿瘤细胞和正常干细胞中的关键调控作用提示lincRNA可能对CSCs也起着重要的调控作用。我们实验发现lincRNA- Bladder Cancer Stem Cell Associated 1(lincRNA-BCSCA1)在膀胱CSCs中高表达，上下调lincRNA-BCSCA1后，膀胱CSCs的干性相应地明显增加或减弱。进一步免疫共沉淀证明lincRNA-BCSCA1和PRC2的EZH2结合，通过转录组测序等发现lincRNA-BCSCA1通过PRC2抑制Smad1、Smad5和p21表达，从而维持膀胱癌干细胞的自我更新，因此，lincRNA-BCSCA1有望成为膀胱癌诊断的新标记物和治疗新靶点。