lincRNA-LBCS结合hnRNP K抑制膀胱癌干细胞的自我更新和化疗耐药的机制研究

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. However, the roles of lincRNAs in cancer stem cell are remain largely unknown. Our previous study found that lincRNA-LBCS is decreased in expression in bladder CSCs. Overexpression or knockdown of linc-LBCS significantly inhibited or enhanced the self-renewal and chemoresistance of bladder CSCs in vitro. Furthermore, we identified that linc-LBCS binds to hnRNPK, a menber of heterogeneous nuclear ribonucleoprotein, by RNA pull down and mass spectrometry. Therefore, we suppose a new mechanism that linc-LBCS induces hnRNPK to regulate a serial gene transcription and alternative splicing to surpress the self-renewal and chemoresistance of bladder CSCs. To gain the proof of linc-LBCS regulate self-renewal and chemoresistance of bladder CSCs by hnRNPK, we will perform animal experiments, co-immunoprecipitation and sequencing analysis. This study is aim to elucidate the function and mechanism of linc-LBCS in bladder CSCs and how they modulate the target genes by binding hnRNPK, in order to identify the new targets for bladder cancer stem cell targeting therapy and the clinical significance of linc-LBCS 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)在肿瘤细胞中起关键的调控作用，但lincRNA在CSCs的作用和机制未见报道。我们预实验发现linc-LBCS在膀胱CSCs中低表达，并抑制膀胱CSCs的干性和化疗耐药功能。RNA pulldown证明linc-LBCS与hnRNPK结合，由此我们提出linc-LBCS调控膀胱CSCs干性和耐药新机制：linc-LBCS通过结合hnRNPK，调控一系列基因的转录和选择性剪接，从而抑制膀胱CSCs的自我更新和化疗耐药。本研究拟进一步采用动物实验，免疫共沉淀和高通量测序等技术，获得linc-LBCS通过hnRNPK调控膀胱CSCs自我更新和化疗耐药的可靠证据，为发现膀胱癌的新标记物和治疗新靶点提供科学依据，确定linc-LBCS在膀胱癌复发、耐药和预后中的意义

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)在肿瘤细胞中起关键的调控作用，但lincRNA在CSCs的作用和机制未见报道。本研究发现linc-LBCS在膀胱CSCs中低表达，并抑制膀胱CSCs的干性和化疗耐药功能。RNA pulldown证明linc-LBCS与hnRNPK/EZH2复合体结合，进一步发现linc-LBCS募集hnRNPK/EZH2复合体到SOX2启动子上，抑制SOX2的表达，从而抑制膀胱CSCs的自我更新和化疗耐药。因此，linc-LBCS有望成为膀胱癌诊断的新标记物和治疗新靶点。