胶质瘤中长链非编码RNA HOTAIR功能网络的解析及其分子机制的研究

前期工作对220例胶质瘤患者临床资料和组织样本基因表达谱研究发现，长链非编码RNA-HOTAIR是胶质瘤独立预后因子；其表达水平与β-catenin转录依赖的胶质瘤分子分型密切相关；与胶质瘤组织中细胞周期蛋白的表达呈正相关。 本项目在对上述样本mRNA/lncRNA表达谱分析基础上，研究HOTAIR通过PRC2/LSD1对细胞周期蛋白的正向调控作用；以胶质瘤细胞中HOTAIR敲除后全转录组测序为基础，在编码基因和短非编码RNA(miRNA与snoRNA)两个层面构建HOTAIR复杂功能网络，研究HOTAIR与mRNA/miRNA/snoRNA 间互作关系；阐明HOTAIR通过调节PKM2参与β-catenin调控细胞周期的分子机制，并探索HOTAIR通过调节某些snoRNA对细胞周期的调控作用。 本研究可揭示HOTAIR对细胞周期调控的分子机制，为发现新的胶质瘤临床标志分子提供实验依据。

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 . It's reported non-coding RNAs and mRNAs are extensively involved in the pathobiology and malignant progression of various kinds of cancer. We profiled the lncRNA expression signatures in 220 gliomas， and for the first time in glioma,identified that expression of HOTAIR was positivetly correlated with glioma grade and poor prognosis. Multivariate Cox regression analysis revealed that HOTAIR was an independent prognostic factor in GBM patients. GSEA analysis indicated that HOTAIR regulateing-gene-sets were enriched in cell cycle progression. Based on our previous study, we first aim to investigate the mechanism of functional domain of HOTAIR positively promote cell cycle progression through PRC2 or LSD1 complex.Second, we use a cell knock-out model system and whole transcriptom sequencing thachology to establish the comprehensive regulatory network of HOTAIR on both mRNA and short non-coding RNA (miRNA and snoRNA). Next we plan to identify the mechanism of HOTAIR-short non-coding RNA network, whick can modulate the transcriptional activity of β-catenin pathway through neuclear recrutment of PKM2 and β-catenin .Moreover,a molecular connection of SNORNA and cell cycle progression will be further investigated. The present study may provide insides for understanding the comprehensive networks of HOTAIR on cell cycle progression as well as β-catenin pathway in glial cancers. Morever, it will provide rationals for a new biomarker and treatment stratgy in gliomas.