长链非编码RNA MEG3及其甲基化在胶质瘤发生发展中的调控机制研究

The loss of long non-coding RNA MEG3 (lncRNA MEG3) due to methylation of lncRNA MEG3 promoter was found in diverse types of cancers including neuroblastoma, meningioma and hepatocellular carcinoma , suggesting that lncRNA MEG3 is a potential tumor suppressor molecule. Applicants preliminary findings that lncRNA MEG3 was expressed in gliomas tissues and several glioma cells, its expression levels were low compared to that in the normal samples. In addition, hypermethylation of lncRNA MEG3 was found in gliomas. The enforced lncRNA MEG3 expression inhibited the proliferation of U87 glioma cells. Based on previous work, the project will combine with glioma model in nude mice in vivo and glioma cell lines in vitro by gene transfection, RNAi and methylation-specific PCR technology, and DNA methylation inhibitor. We will study the effect of lncRNA MEG3 on the migration, invasion and angiogenesis of glioma cells, and investigate its molecular mechanisms, and gain insights into the expression of lncRNA MEG3 mediated by DNA methylation in gliomas. This project will have important implications in revealing the molecular mechanism of pathogenesis of gliomas, and improving the rational design of therapeutic drugs for the treatment of gliomas.The study has not been reported in the world.

长链非编码RNA MEG3(lncRNA MEG3)在神经母细胞瘤、脑膜瘤及肝癌等肿瘤中因启动子甲基化而表达显著下调或缺失，推测其可能为一新的肿瘤抑制非编码RNA分子。申请人前期研究发现lncRNA MEG3在脑胶质瘤组织和多株胶质瘤细胞中表达下调，且lncRNA MEG3在脑胶质瘤组织中发生高甲基化，过表达lncRNA MEG3抑制U87胶质瘤细胞增殖。本研究拟在以往研究工作的基础上，采用基因转染、RNAi及甲基化特异性PCR 等技术以及DNA甲基化抑制剂，将体外胶质瘤细胞株与体内裸鼠胶质瘤模型相结合，研究lncRNA MEG3对胶质瘤细胞迁移、侵袭及血管形成等恶性表型的影响，并调查其分子机制，以及探讨DNA甲基化调控lncRNA MEG3对胶质瘤恶性表型的影响。该研究对进一步揭示胶质瘤发病的分子机制、设计合理的治疗药物，提高胶质瘤的治疗水平具有重要的意义。此项研究国内外未见报告。

胶质瘤恶性程度高、预后差，多以侵袭性生长为主，是目前神经外科临床的重要挑战。申请者研究发现长链非编码RNA MEG3甲基化调控胶质瘤细胞的增殖和凋亡，且在胶质瘤细胞中DNMT1介导MEG3的甲基化。我们进一步探讨了miR-200家族成员miR-141和miR-200a在胶质瘤中的作用及相关分子机制。研究发现DNMT1调控miR-141的甲基化促进胶质瘤恶性表型，Hotair与miR-141结合调控其靶基因SKA2。LncRNA-ATB与miR-200a竞争性结合调控其靶基因TGF-β2进而影响胶质瘤细胞的恶性表型。本研究对进一步揭示胶质瘤发病的分子机制、个体化治疗新靶点提供理论依据。