非编码RNAs与膀胱癌发病、预后关系的分子流行病学及ceRNA机制的研究

Bladder cancer (BC), as the most common malignant tumor of the urinary system, has become a worldwide public health problem. Therefore, it is essential to find reliable biomarkers that can be used for early diagnosis and prognosis assessment of BC as well as exploring its role in the pathogenesis and prognosis. MiRNAs, lncRNAs and circRNAs, as important non-coding RNAs, are involved in the pathogenesis and prognosis of BC. However, there is still no research on the relationship between miRNAs, lncRNAs, circRNAs and the incidence and prognosis of BC in epidemiology with big sample size. The aim of this study is to screen miRNAs, lncRNAs and circRNAs that can be utilized in diagnosis and prognosis assessment of BC based on the Case-control study and Cohort study and evaluated the role of miRNAs, lncRNAs, circRNAs and the interaction between non-code RNAs and environment in the the occurrence and prognosis of BC . In addition , the ceRNA mechanisms between miRNAs and lncRNAs, circRNAs were explored and validated. The proposed findings will utilized as the biomarkers for diagnosis and prognosis assessment of BC.

膀胱癌是泌尿系最常见恶性肿瘤，已成为世界性公共卫生问题，因此寻找可用于早期诊断和评价预后的可靠生物标志物，并探讨其在发病与预后中的作用机制对于膀胱癌的个体化精准防治至关重要。MiRNAs、lncRNAs与circRNAs参与了膀胱癌的发病及预后，但在人群流行病学研究中探讨miRNAs、lncRNAs、circRNAs与膀胱癌发病及预后关系的研究尚属空白。本研究拟在国内外率先在大样本人群中筛选能用于膀胱癌诊断及预后评价的miRNAs、lncRNAs与circRNAs生物标志物，观察其（单独或联合）与膀胱癌发生和预后的关系，并探讨其（单独或联合）与环境交互作用与膀胱癌发生和预后的关系，同时从ceRNAs角度探讨miRNAs、lncRNAs与circRNAs在膀胱癌发生和预后中的作用机制。本研究的完成可为膀胱癌的早期诊断和预后评价提供可靠的非编码RNAs生物标志物，并为膀胱癌的治疗提供新靶点。

膀胱癌发生、发展机制尚不清楚，缺乏确切的分子生物标志物和有效的治疗靶点。非编码RNAs参与了膀胱癌的发生与预后，本课题从非编码RNAs与膀胱癌发生、预后关系的分子流行病学及 ceRNAs 作用机制的角度探讨了非编码RNAs与膀胱癌的关系，为膀胱癌的发生和预后评价提供新型生物标志物和治疗靶点。①lncRNA XIST在膀胱癌细胞系中表达上调，但在膀胱癌组织中表达下调，lncRNA PICSAR在膀胱癌细胞系和组织中表达均上调，hsa-miR-129-5p、hsa-miR-378g在膀胱癌细胞系和组织中表达均下调，TNFSF10在膀胱癌细胞系和组织中表达均上调，MECP2在膀胱癌细胞系表达上调；②LncRNA XIST可以竞争性结合hsa-miR-129-5p调控TNFSF10的表达，lncRNA PICSAR在膀胱癌中作为hsa-miR-378g的分子海绵调控MECP2的表达；③LncRNA XIST表达水平与性别有关， hsa-miR-129-5p表达水平与病理分级呈正相关；lncRNA PICSAR和Hsa-miR-378g表达水平与TNM分期呈正相关；④LncRNA XIST、hsa-miR-129-5p和TNFSF10的最佳截断值分别为0.281、0.417、1.638，灵敏度分别为63.3%、80.0%、90.0%，特异度分别为91.7%、76.7%、55.0%，AUC分别为0.739、0.850、0.753。三者联合AUC为0.900，灵敏度为83.3%，特异度为86.7%；⑤Hsa_circ_0004163在膀胱癌细胞系、组织和全血中表达均上调，hsa-miR-585-3p在膀胱癌细胞系和组织中表达均下调，SPOCK1在膀胱癌细胞系和全血中表达均上调；⑥Hsa_circ_0004163通过吸附hsa_miR-585-3p调控SPOCK1的表达；⑦Hsa-miR-585-3p表达水平与T stage呈负相关；⑧Hsa_circ_000416高表达与膀胱癌患者3年生存期有关。本项目的完成可能为膀胱癌的早期诊断和预后评价提供可靠的非编码RNAs生物标志物，并为膀胱癌的治疗提供新的靶点。