Abstract
BackgroundThe incidence of cholangiocarcinoma (CCA) has risen in recent years, and it has become a significant health burden worldwide. However, the mechanisms underlying tumorigenesis and progression of this disease remain largely unknown. An increasing number of studies have demonstrated crucial biological functions of epigenetic modifications, especially DNA methylation, in CCA. The present study aimed to identify and analyze methylation-regulated differentially expressed genes (MeDEGs) involved in CCA tumorigenesis and progression by bioinformatics analysis.MethodsThe gene expression profiling dataset (GSE119336) and gene methylation profiling dataset (GSE38860) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were identified using the limma packages of R and GEO2R, respectively. The MeDEGs were obtained by overlapping the DEGs and DMGs. Functional enrichment analyses of these genes were then carried out. Protein–protein interaction (PPI) networks were constructed using STRING and visualized in Cytoscape to determine hub genes. Finally, the results were verified based on The Cancer Genome Atlas (TCGA) database.ResultsWe identified 98 hypermethylated, downregulated genes and 93 hypomethylated, upregulated genes after overlapping the DEGs and DMGs. These genes were mainly enriched in the biological processes of the cell cycle, nuclear division, xenobiotic metabolism, drug catabolism, and negative regulation of proteolysis. The top nine hub genes of the PPI network were F2, AHSG, RRM2, AURKB, CCNA2, TOP2A, BIRC5, PLK1, and ASPM. Moreover, the expression and methylation status of the hub genes were significantly altered in TCGA.ConclusionsOur study identified novel methylation-regulated differentially expressed genes (MeDEGs) and explored their related pathways and functions in CCA, which may provide novel insights into a further understanding of methylation-mediated regulatory mechanisms in CCA.
Highlights
The incidence of cholangiocarcinoma (CCA) has risen in recent years, and it has become a significant health burden worldwide
Identification of methylation-regulated differentially expressed genes (MeDEGs) in CCAThe limma packages of R and GEO2R were used to screen for differentially expressed genes (DEGs) and differentially methylated genes (DMGs), respectively
We found that hypermethylated genes predominantly participated in metabolism-related pathways, including general metabolic pathways, drug or xenobiotic metabolism by cytochrome P450, and cholesterol metabolism
Summary
The incidence of cholangiocarcinoma (CCA) has risen in recent years, and it has become a significant health burden worldwide. The mechanisms underlying tumorigenesis and progression of this disease remain largely unknown. An increasing number of studies have demonstrated crucial biological functions of epigenetic modifications, especially DNA methylation, in CCA. The present study aimed to identify and analyze methylationregulated differentially expressed genes (MeDEGs) involved in CCA tumorigenesis and progression by bioinformatics analysis. Cholangiocarcinoma (CCA) is a fatal malignancy originating from the epithelial cells of the biliary tree [1]. About one-third of CCA patients are eligible for surgery; most patients are often diagnosed with unresectable or metastatic disease [4]. The incidence of CCA seems to be on the rise, especially for intrahepatic tumors [6]. Exploring the molecular mechanisms underlying the pathogenesis and development of CCA is urgently needed
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