长链非编码RNA MIR155HG多重调控KRAS信号通路影响胶质瘤恶性进展的机理研究

In the past decade, emerging data indicate that long non-coding RNA can have important biological functions and roles in human malignant tumors. However the study on specific relationship between lncRNA and gene regulatory network is still at its preliminary stage. In previous studies, we identified that lncRNA MIR155HG was closely associated with glioma malignant progression, as well as it may infect the KRAS signaling pathway via multiple different approaches. In this program, we firstly plan to investigate the mechanism of MIR155HG may act as a competing endogenous RNA, effectively becoming a sink for miR-193a-3p, thereby lead to the activation of KRAS signaling pathway; Secondly, we aim to demonstrate that MIR155HG may epigenetically regulate miR-214, which can diret targeting KRAS, by binding to EZH2. The present study may provide insides for understanding the transcriptional regulation and epigenetically regulation mechanism of MIR155HG/KRAS pathway and MIR155HG may participate in the multiple modes that modulates glioma malignant progression. Moreover, it will also provide rational theories and research methods for the mechanism of lncRNA.

长链非编码RNA（lncRNA）在胶质瘤中功能网络的相关研究还处于起步阶段。课题组前期研究发现MIR155HG是与胶质瘤恶性进展密切相关的lncRNA分子，并推断其可能通过多种模式参与KRAS信号通路激活调控，提出科学假说：“MIR155HG可作为分子海绵吸附miR-193a-3p，同时可招募EZH2催化组蛋白H3K27me3影响miR-214转录，通过双重阻断miRNA靶向抑制激活KRAS信号通路”。本次项目拟在结合临床样本验证和体内外实验全面评价MIR155HG的生物学功能和诊断评估价值基础上，解析MIR155HG通过分子海绵和染色质重塑多重模式参与KRAS通路激活调控的分子机理。预期结果将完善胶质瘤相关ncRNA作用及机制，强化lncRNA与miRNA的互作模式和调控网络构建，同时为开发与挖掘肿瘤药物作用靶点提供实验基础。

长链非编码RNA（lncRNA）在胶质瘤中功能网络的相关研究还处于起步阶段。课题组前期研究发现MIR155HG是与胶质瘤恶性进展密切相关的lncRNA分子，并推断其可能通过多种模式参与KRAS信号通路激活调控，在本项目研究工作中，项目组取得一系列研究成果：①明确胶质母细胞瘤患者中MIR155HG高表达可以作为一个独立的预后不良因子；②MIR155HG通过生成miR-155-5p和miR-155-3p，调控其下游直接靶标PCDH9和PCDH7，抑制Wnt/β-catenin通路；同时miR155HG可以作为miR-185的竞争内源RNA（分子海绵）抑制miR-185对其直接靶向分子ANXA2的沉默作用，产生抑癌效应；③筛选获得作用于MIR155HG/MIR-155靶向轴上的强效小分子抑制剂NSC141562，有可能成为治疗胶质瘤的候选靶向药物。项目将lncRNA/miRNA交互模式研究、分子信号网络解析、计算机辅助药物设计、肿瘤原位动物模型构建等理念和方法高度整合，从细胞水平、体内实验到体外实验，多学科、多层次、多角度，针对性地研究ncRNA转录调控与功能在胶质瘤EMT进程中的作用，探索MIR155HG/miR-155特异性小分子抑制剂用于胶质瘤靶向治疗的可行性。