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Abstract：
Glioma is an extremely aggressive malignant neoplasm of the central nervous system. MicroRNA (miRNA) are known to bind to specific target mRNA to regulate post-transcriptional gene expression and are, therefore, currently regarded as promising biomarkers for glioma diagnosis and prognosis. The aim of the present study was to examine the pathogenesis and potential molecular markers of glioma by comparing the differential expression of miRNA and mRNA between glioma tissue and peritumor brain tissue. We explored the impact of screened core miRNA and mRNA on cell proliferation, invasion, and migration of glioma. An miRNA expression profile dataset (GSE90603) and a transcriptome profile dataset (GSE90598) were downloaded from combined miRNA-mRNA microarray chips in the Gene Expression Omnibus (GEO) database. Overall, 59 differentially expressed miRNAs (DEMs) and 419 differentially expressed genes (DEGs) were identified using the R limma software package. FunRich software was used to predict DEM target genes and miRNA-gene pairs, and Perl software was used to find overlapping genes between DEGs and DEM target genes. There were 129 overlapping genes regulated by nine miRNAs between target genes of the DEMs and DEGs. The Chinese Glioma Genome Atlas(CGGA) was analyzed in order to identify miRNAs with diagnostic and prognostic significance. MiR-139-5p, miR-137, and miR-338-3p were validated to be significantly linked to prognosis in glioma patients. Finally, we validated that miR-139-5p affected glioma malignant biological behavior via targeting gamma-aminobutyric acid A receptor alpha 1(GABRA1) through rescue experiments. Low miR-139-5p expression was correlated with survival probability and World Health Organization (WHO) grade. MiR-139-5p overexpression inhibited cell proliferation, migration, and invasion of glioma in vitro. GABRA1 was identified as a functional downstream target of miR-139-5p. Decreased GABRA1 expression was related to similar biological roles as miR-139-5p overexpression while upregulation of GABRA1 effectively reversed the inhibition effects of miR-139-5p. These results demonstrate a novel axis for miR-139-5p/GABRA1 in glioma progression and provide potential prognostic predictors and therapeutic target for glioma patients.
摘要：
胶质瘤是一种极具侵袭性的中枢神经系统恶性肿瘤。已知MicroRNA(miRNA)与特定靶mRNA结合以调节转录后基因表达,因此,目前被认为是胶质瘤诊断和预后的有希望的生物标志物。本研究的目的是通过比较胶质瘤组织和瘤周脑组织之间miRNA和mRNA的差异表达来检查胶质瘤的发病机制和潜在的分子标志物。我们探索了筛选的核心miRNA和mRNA对细胞增殖的影响，入侵,和神经胶质瘤的迁移。从基因表达综合(GEO)数据库中的组合miRNA-mRNA微阵列芯片下载miRNA表达谱数据集(GSE90603)和转录组谱数据集(GSE90598)。总的来说,使用Rlimma软件包鉴定了59个差异表达的miRNA（DEM）和419个差异表达的基因（DEG）。FunRich软件用于预测DEM靶基因和miRNA-基因对,并利用Perl软件寻找DEGs和DEM靶基因之间的重叠基因。DEM和DEGs的靶基因之间有129个重叠基因受9个miRNAs调控。分析中国胶质瘤基因组图谱(CGGA)以鉴定具有诊断和预后意义的miRNA。MiR-139-5p,miR-137和miR-338-3p被证实与神经胶质瘤患者的预后显著相关。最后,我们通过拯救实验验证了miR-139-5p通过靶向γ-氨基丁酸A受体α1(GABRA1)影响神经胶质瘤恶性生物学行为.miR-139-5p低表达与生存概率和世界卫生组织(WHO)分级相关。MiR-139-5p过表达抑制细胞增殖,迁移,和胶质瘤的体外侵袭。GABRA1被鉴定为miR-139-5p的功能性下游靶标。GABRA1表达的降低与miR-139-5p过表达的生物学作用相似，而GABRA1的上调有效逆转了miR-139-5p的抑制作用。这些结果证明了miR-139-5p/GABRA1在神经胶质瘤进展中的新轴，并为神经胶质瘤患者提供了潜在的预后预测因子和治疗靶标。
