鉴定血清外泌体miR-98-5p、miR-183-5p、miR-323-3p和miR-19b-3p作为胶质母细胞瘤患者的潜在生物标志物并研究其机制。

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.

作者信息

Yang Qi, Wei Bo, Peng Chuangang, Wang Le, Li Chang

机构信息

Department of Gynecology and Obstetrics, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.

Departments of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.

出版信息

Curr Res Transl Med. 2022 Jan;70(1):103315. doi: 10.1016/j.retram.2021.103315. Epub 2021 Nov 24.

DOI:10.1016/j.retram.2021.103315

PMID:34837760

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), hsa05200:Pathways in cancer (CASP3) and hsa04068:FoxO 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.

摘要

背景

外泌体微小RNA（miRNA）作为癌症潜在的生物标志物和治疗靶点，已引起越来越多的关注，然而，与胶质母细胞瘤（GBM）相关的外泌体miRNA报道仍很少。本研究旨在筛选GBM患者血清中关键的外泌体miRNA，并探讨其可能的机制。

方法

从基因表达综合数据库（GSE112462和GSE122488）下载GBM患者和正常对照的血清外泌体miRNA谱数据集。使用limma方法鉴定差异表达的miRNA（DEM）。通过受试者工作特征（ROC）曲线分析评估其诊断价值。通过miRwalk 2.0数据库预测DEM的靶基因。使用DAVID数据库进行功能富集分析。使用TCGA测序数据和免疫组织化学验证靶基因的表达和预后。

结果

两个数据集中共有7个DEM，其中hsa-miR-183-5p和hsa-miR-98-5p以及has-miR-323-3p或has-miR-19b-3p构成了区分GBM与对照的诊断特征，ROC曲线下面积接近1。MAPK8IP1/FAM175B、OSMR/CASP3、PTPN2和FBXO32可能分别是hsa-miR-183-5p、hsa-miR-98-5p、has-miR-323-3p和has-miR-19b-3p的潜在靶标。功能分析表明，所有这些靶基因都参与细胞增殖和相关信号通路[细胞增殖的正调控（OSMR）、RNA聚合酶II启动子转录的负调控（PTPN2）、细胞分裂（FAM175B）、转录调控、DNA模板化（MAPK8IP1）、hsa05200：癌症通路（CASP3）和hsa04068：FoxO信号通路（FBXO32）]。在GBM组织中，OSMR、CASP3、PTPN2和FBXO32的蛋白质和（或）mRNA表达水平被验证为上调，而MAPK8IP1和FAM175B下调。此外，OSMR、CASP3、PTPN2和FBXO32与患者预后相关。