脑胶质瘤中Hedgehog通路介导的长链非编码RNA-MEG3作用机制的研究

项目名称： 脑胶质瘤中Hedgehog通路介导的长链非编码RNA-MEG3作用机制的研究

项目编号： No.81502404

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 杜文众

作者单位： 哈尔滨医科大学

项目金额： 18万元

中文摘要： 课题组前期工作发现，利用慢病毒介导的siRNA技术敲低核转录因子GLI1的表达谱结果显示，长链非编码RNA-MEG3表达显著上调；进一步对220例胶质瘤患者临床资料和组织样本基因表达谱分析发现，MEG3在胶质瘤中呈低表达，与级别呈负相关。.本项目在上述基础上，验证胶质瘤中MEG3表达、与肿瘤级别、预后的关系及敲低GLI1后对MEG3表达的影响；研究GLI1作用DNMT1对MEG3负向调控作用；探索MEG3转录调控P53的作用机制及对p53通路活性及下游靶基因（p21、GDF15）的影响；研究不同MEG3表达在体内外对胶质瘤增殖、凋亡、干细胞“干性”及TMZ敏感性的作用；探讨P53对GLI1表达及转录活性影响，解析MEG3/P53/GLI1调控环路在临床胶质瘤早期诊断及预后判断中的意义；.本课题可揭示Hedgehog通路介导下MEG3发挥作用的分子机制，为胶质瘤的靶向治疗提供新的理论依据。

中文关键词： 胶质瘤；长链非编码RNA；转录调控；信号转导通路；增殖

英文摘要： Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Patients with newly diagnosed glioblastoma have a median survival of approximately 1 year which mainly resulted from its poor responses to all therapeutic modalities .Our previous studies showed that aberrant activation of Hedgehog signaling pathway has been observed in gliomas and inhibition of the pathway’s activity by drugs or miRNAs affected the biological behaviors of glioma cells and the self-renewal of tumor stem cells. After we used RNA interference technology mediated by lentivirus vectors blocking the hedgehog signaling activity, we found that according to the expression profile ,the long non-coding RNA-MEG3 upregulated. Meanwhile, We profiled the lncRNA expression signatures in 220 gliomas and found that expression of MEG3 was negatively correlated with glioma grade and poor prognosis..Based on the above results of the gene expression profiles,we aimed to verify the expression of MEG3 in gliomas specimens and analysed the correlation between MEG3 and GLI1 genes. Subsequently, we intended to investigate the negative role of GLI1 on MEG3 mediated by DNMT1. We plan to identify the mechanism of MEG3 in gliomas,which may modulate the activity of P53 pathway and its downstream target genes ( p21,GDF15) through activation of P53. Moreover, we would also like to investigate the gliomas biological behaviors including proliferation, apoptosis, stemness and the sensitivity to TMZ after modulation of MEG3 in vitro and vivo. Finally, we aimed to explore the effect of P53 on GLI1’s expression and trans- criptional activity..The present study may provide insides for understanding the comprehensive networks of MEG3/P53/GLI1 on glioma progression. Morever, it will provide a new treatment strategy in gliomas.

英文关键词： glioma;long non-coding RNA;transcription regulation;signaling pathway;proliferation