Zhang Cheng, Zhang Bingye, Meng Di, Ge Chunlin
1Department of Pancreatic and Biliary Surgery, The First Hospital of China Medical University, Shenyang, 110001 Liaoning China.
2Department of Gerontology, The First Hospital of China Medical University, Shenyang, 110001 Liaoning China.
Cancer Cell Int. 2019 Dec 26;19:352. doi: 10.1186/s12935-019-1080-y. eCollection 2019.
The 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.
The 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.
We 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.
Our 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.
近年来，胆管癌（CCA）的发病率呈上升趋势，已成为全球一项重大的健康负担。然而，该疾病发生和进展的潜在机制在很大程度上仍不清楚。越来越多的研究表明，表观遗传修饰，尤其是DNA甲基化，在CCA中具有关键的生物学功能。本研究旨在通过生物信息学分析，鉴定和分析参与CCA发生和进展的甲基化调控差异表达基因（MeDEGs）。
从基因表达综合数据库（GEO）获取基因表达谱数据集（GSE119336）和基因甲基化谱数据集（GSE38860）。分别使用R语言的limma软件包和GEO2R软件鉴定差异表达基因（DEGs）和差异甲基化基因（DMGs）。通过对DEGs和DMGs进行重叠分析获得MeDEGs。随后对这些基因进行功能富集分析。使用STRING构建蛋白质-蛋白质相互作用（PPI）网络，并在Cytoscape中进行可视化以确定枢纽基因。最后，基于癌症基因组图谱（TCGA）数据库对结果进行验证。
在对DEGs和DMGs进行重叠分析后，我们鉴定出98个高甲基化、下调基因和93个低甲基化、上调基因。这些基因主要富集于细胞周期、核分裂、异源物质代谢、药物分解代谢以及蛋白水解的负调控等生物学过程。PPI网络的前九个枢纽基因分别为F2、AHSG、RRM2、AURKB、CCNA2、TOP2A、BIRC5、PLK1和ASPM。此外，枢纽基因的表达和甲基化状态在TCGA中发生了显著改变。
我们的研究鉴定出了新的甲基化调控差异表达基因（MeDEGs），并探索了它们在CCA中的相关途径和功能，这可能为进一步理解CCA中甲基化介导的调控机制提供新的见解。
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