Construction of Potential Glioblastoma Multiforme-Related miRNA-mRNA Regulatory Network.

Weiyang Lou,Bisha Ding,Weimin Fan,Liang Xu

doi:10.3389/fnmol.2019.00066

Abstract

Background: Glioblastoma multiforme (GBM), the most common and aggressive human malignant brain tumor, is notorious for its limited treatment options and poor prognosis. MicroRNAs (miRNAs) are found to be involved in tumorigenesis of GBM. However, a comprehensive miRNA-mRNA regulatory network has still not been established.Methods: A miRNA microarray dataset (GSE90603) was obtained from GEO database. Then, we employed GEO2R tool to perform differential expression analysis. Potential transcription factors and target genes of screened differentially expressed miRNAs (DE-miRNAs) were predicted. The GBM mRNA dataset were downloaded from TCGA database for identifying differentially expressed genes (DEGs). Next, GO annotation and KEGG pathway enrichment analysis was conducted. PPI network was then established, and hub genes were identified via Cytoscape software. The expression and prognostic roles of hub genes was further evaluated.Results: Total 33 DE-miRNAs, consisting of 10 upregulated DE-miRNAs and 23 downregulated DE-miRNAs, were screened. SP1 was predicted to potentially regulate most of screened DE-miRNAs. Three thousand and twenty seven and 3,879 predicted target genes were obtained for upregulated and downregulated DE-miRNAs, respectively. Subsequently, 1,715 upregulated DEGs and 1,259 downregulated DEGs were identified. Then, 149 and 295 potential downregulated and upregulated genes commonly appeared in target genes of DE-miRNAs and DEGs were selected for GO annotation and KEGG pathway enrichment analysis. The downregulated genes were significantly enriched in cGMP-PKG signaling pathway and calcium signaling pathway whereas the upregulated genes were enriched in pathways in cancer and PI3K-Akt signaling pathway. Construction and analysis of PPI network showed that STXBP1 and TP53 were recognized as hub genes with the highest connectivity degrees. Expression analytic result of the top 20 hub genes in GBM using GEPIA database was generally identical with previous differential expression analysis for TCGA data. EGFR, PPP3CB, and MYO5A expression was significantly associated with patients' OS.Conclusions: In this study, we established a potential GBM-related miRNA-mRNA regulatory network, which explores a comprehensive understanding of the molecular mechanisms and provides key clues in seeking novel therapeutic targets for GBM. In the future, more experiments need to be performed to validate our current findings.

Highlights

Glioblastoma multiforme (GBM), a highly prevalent malignant astrocytic tumor, is composed of poorly differentiated neoplastic astrocytes, accounting for nearly 70% of all diffuse astrocytic tumors and 10–15% of all intracranial neoplastic lesions (Ohgaki and Kleihues, 2005)
We searched datasets focusing on the miRNA expression in GBM in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database
The dysregulation of miRNAmRNA regulatory network in brain leads to a variety of human diseases, such as Alzheimer’s disease (Bekris et al, 2013; Bekris and Leverenz, 2015; Hara et al, 2017), Parkinson’s disease (Burgos et al, 2014), cerebral infarction (Liang et al, 2018) and ischemic neuronal injury (Feng et al, 2018)

Summary

Introduction

Glioblastoma multiforme (GBM), a highly prevalent malignant astrocytic tumor, is composed of poorly differentiated neoplastic astrocytes, accounting for nearly 70% of all diffuse astrocytic tumors and 10–15% of all intracranial neoplastic lesions (Ohgaki and Kleihues, 2005). GBM is generally ranked as the most aggressive type among all brain tumors according to WHO classification (Møller et al, 2013). With the highly invasive nature, most of patients with GBM will eventually recurs after surgical resection, owing to the impossibility that all tumors cells in patients are completely removed (Koo et al, 2012). Glioblastoma multiforme (GBM), the most common and aggressive human malignant brain tumor, is notorious for its limited treatment options and poor prognosis. MicroRNAs (miRNAs) are found to be involved in tumorigenesis of GBM. A comprehensive miRNA-mRNA regulatory network has still not been established

Methods

Results

Discussion

Conclusion