Prognostic values and prospective pathway signaling of MicroRNA-182 in ovarian cancer: a study based on gene expression omnibus (GEO) and bioinformatics analysis

Abstract

Background: Ovarian carcinoma (OC) is a common cause of death among women with gynecological cancer. MicroRNAs (miRNAs) are believed to have vital roles in tumorigenesis of OC. Although miRNAs are broadly recognized in OC, the role of has-miR-182-5p (miR-182) in OC is still not fully elucidated.

Methods: We evaluated the significance of miR-182 expression in OC by using analysis of a public dataset from the Gene Expression Omnibus (GEO) database and a literature review. Furthermore, we downloaded three mRNA datasets of OC and normal ovarian tissues (NOTs), GSE14407, GSE18520 and GSE36668, from GEO to identify differentially expressed genes (DEGs). Then the targeted genes of hsa-miR-182-5p (TG_miRNA-182-5p) were predicted using miRWALK3.0. Subsequently, we analyzed the gene overlaps integrated between DEGs in OC and predicted target genes of miR-182 by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network and the prognostic effects of the hub genes were analyzed.

Results: A common pattern of up-regulation for miR-182 in OC was found in our review of the literature. A total of 268 DEGs, both OC-related and miR-182-related, were identified, of which 133 genes were discovered from the PPI network. A number of DEGs were enriched in extracellular matrix organization, pathways in cancer, focal adhesion, and ECM-receptor interaction. Two hub genes, MCM3 and GINS2, were significantly associated with worse overall survival of patients with OC. Furthermore, we identified covert miR-182-related genes that might participate in OC by network analysis, such as DCN, AKT3, and TIMP2. The expressions of these genes were all down-regulated and negatively correlated with miR-182 in OC.

Conclusions: Our study suggests that miR-182 is essential for the biological progression of OC.

Keywords: Differentially expressed genes; Functional enrichment analysis; Ovarian cancer; Protein-protein interaction; Survival analysis; miR-182.

Fig. 1

Flow chart of study selection for GEO dataset

Fig. 2

Expression of miR-182 in ovarian cancer and normal ovarian tissues in GEO datasets. OV: ovarian cancer tissue; Normal: normal ovarian tissue; miR-182: hsa-miR-182-5p

Fig. 3

Forest plot (A) and funnel plot (B) of the combined SMD for hsa-miR-182-5p expression between ovarian cancer and normal ovarian tissue by the random effects models

Fig. 4

Flow chart of study selection for the literature review

Fig. 5

Volcano plot of detectable genome-wide mRNA profiles in ovarian cancer tissue and normal ovarian tissue samples from GSE14407, GSE18520, and GSE36668, respectively. Blue and red plots represent aberrantly expressed mRNAs with P<0.05 and |log(FC)|>1. Blue plots indicate up-regulated genes, red plots indicate down-regulated genes and green plots indicate normally expressed mRNAs. The x-axis is the fold-change value between the expression of mRNAs in ovarian cancer tissues and normal ovarian tissues. The y-axis is the -log10 of the adj.P.Value for each mRNA, representing the strength of the association. adj.P.Value, adjusted P value; FC, fold change

Fig. 6

Venn plots of hsa-miR-182-5p-related differentially expressed genes from four datasets ( GSE14407, GSE18520, GSE36668, and TG_miR-182-5p), the overlapping area corresponds to the commonly identified DEGs. DEGs: differentially expressed genes; TG_miR-182-5p, target genes of hsa-miRNA-182-5p.

Fig. 7

Protein-protein interaction network of hsa-miR-182-5p-related DEGs. Blue nodes stand for up-regulated genes, while red nodes stand for down-regulated genes. The lines represent interaction relationship between nodes. DEGs, differentially expressed genes

Fig. 8

Protein-protein interaction network. (A): Protein-protein interaction network of hube genes of hsa-miR-182-5p-related DEGs. (B): A significant module selected from protein-protein interaction network of hsa-miR-182-5p-related DEGs. Blue nodes stand for up-regulated genes, while red nodes stand for down-regulated genes. The lines represent interaction relationship between nodes. DEGs, differentially expressed genes

Fig. 9

Overall survival analysis of MCM3 and GINS2 expression with prognosis of ovarian cancer patients. The patients with ovarian cancer were divided into two groups (high vs. low), according to the median expression level of MCM3 and GINS2