Identification of serum exosomal miR-98-5p, miR-183-5p, miR-323-3p and miR-19b-3p as potential biomarkers for glioblastoma patients and investigation of their mechanisms.

ABSTRACT

BACKGROUND: Exosomal miRNAs have attracted increasing interest as potential biomarkers and treatment targets for cancers, however, glioblastoma (GBM)-related exosomal miRNAs remain rarely reported. The study aimed to screen crucial serum exosomal miRNAs in GBM patients and explored their possible mechanisms. METHODS: Serum exosomal miRNA profile datasets of GBM patients and normal controls were downloaded from the Gene Expression Omnibus database (GSE112462 and GSE122488). The differentially expressed miRNAs (DEMs) were identified using the limma method. Their diagnostic values were assessed by receiver operating characteristic (ROC) curve analysis. The target genes of DEMs were predicted by the miRwalk 2.0 database. Function enrichment analysis was performed using the DAVID database. The expression and prognosis of target genes were validated using TCGA sequencing data and immunohistochemistry. RESULTS: Seven DEMs were shared in two datasets, among which hsa-miR-183-5p and hsa-miR-98-5p as well as has-miR-323-3p or has-miR-19b-3p constituted a diagnostic signature to distinguish GBM from controls, with the area under the ROC curve nearly approximate to 1. MAPK8IP1/FAM175B, OSMR/CASP3, PTPN2 and FBXO32 may be underlying targets for hsa-miR-183-5p, hsa-miR-98-5p, has-miR-323-3p and has-miR-19b-3p, respectively. Function analysis showed all of these target genes were involved in cell proliferation and related signaling pathways [positive regulation of cell proliferation (OSMR), negative regulation of transcription from RNA polymerase II promoter (PTPN2), cell division (FAM175B), regulation of transcription, DNA-templated (MAPK8IP1), hsa05200Pathways in cancer (CASP3) and hsa04068FoxO signaling pathway (FBXO32)]. The protein and (or mRNA) expression levels of OSMR, CASP3, PTPN2 and FBXO32 were validated to be upregulated, while MAPK8IP1 and FAM175B were downregulated in GBM tissues. Also, OSMR, CASP3, PTPN2 and FBXO32 were associated with patients' prognosis. CONCLUSION: These findings suggest these four exosomal miRNAs may represent potential diagnostic biomarkers and therapeutic targets for GBM.