Identification of genes and pathways involved in malignant pleural mesothelioma using bioinformatics methods

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare tumor in the pleura. This study was carried out to identify key genes and pathways that may be involved in MPM.

Methods: Microarray datasets GSE51024 and GSE2549 were analyzed for differentially expressed genes (DEGs) between normal and MPM tissues. The identified DEGs were subjected to functional analyses using bioinformatics tools.

Results: A total of 276 DEGs were identified, consisting of 187 downregulated and 79 upregulated genes. Gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analysis indicated that the DEGs were enriched in extracellular structure organization, extracellular matrix, and ECM-receptor interaction. Due to high degree of connectivity among 24 hub genes, EZH2 and HMMR are likely to play roles in the carcinogenesis and progression of MPM. The two genes were found over-expressed in MPM tissues. Patients with elevated EZH2 and HMMR expressions had poor overall survival.

Conclusions: EZH2 and HMMR are identified to be the hub genes for MPM and they may be further characterized to better understand the molecular mechanisms underlying the carcinogenesis of MPM.

Keywords: Bioinformatics; Cancer; Differentially expressed genes; Gene expression profile; Microarray; Protein–protein interaction.

Fig. 1

Volcano plot and Venn diagram of DEGs in MPM mRNA expression profiling datasets. Volcano plots of the gene expression data from the a GSE50124, b GSE2549 datasets. DEGs were selected by P < 0.05 and |log2 (fold-change)|> 1.The horizontal axis represents the log2 (fold change) between MPM samples and non-cancerous tissue samples; the vertical axis represents the -log10 (adjusted P-values). The red dots represent the co-upregulated DEGs and the blue dots represent the co-downregulated DEGs. c The grey overlap represents the common DEGs between the two datasets. DEGs differentially expressed genes

Fig. 2

PPI network of the common DEGs constructed using Cytoscape. Rectangles and circles represent up-regulated and down-regulated mRNAs, respectively. The color depth of nodes refers to the log2 (fold-change). PPI network protein–protein interaction network, DEGs differentially expressed genes

Fig. 3

A significant module of hub genes obtained from the PPI network of DEGs using MCODE. PPI network protein–protein interaction network, MCODE molecular complex detection

Fig. 4

GO and KEGG pathway enrichment analysis of the common DEGs. a The top 10 significantly functionally enriched GO terms. Each dot represents a GO term. The dot size represents the count of genes in each term, while colors represent the adjusted P-value. b Four mostly enriched KEGG pathways. Each dot represents a KEGG pathway. The dot size represents the count of genes in each term, while colors represent the adjusted P-value. GO Gene Ontology, KEGG Kyoto Encyclopedia of Genes and Genomes, DEG differentially expressed genes, BP biological process, MF molecular function, CC cell component

Fig. 5

GO and KEGG pathway enrichment analysis for the common genes based on the gene enrichment degree. a BP, b MF, c CC and d KEGG pathway analysis. The genes were arranged in circles clockwise direction according to their enrichment degree. The left rectangular colors represent log2 (fold-change) of the common genes. The right rectangular colors represent enriched terms. GO Gene Ontology, KEGG Kyoto Encyclopedia of Genes and Genomes, BP biological process, MF molecular function, CC cell component

Fig. 6

mRNA expression levels of EZH2 (a) and HMMR (b) in MPM, lung and pleura tissue samples in the ONCOMINE database

Fig. 7

UALCAN overall survival analysis of MPM patients with high and low expression of EZH2 (a) and HMMR (b)