Abstract
Esophageal adenocarcinoma (EAC) is a deadly cancer with high mortality rate, especially in economically advanced countries, while Barrett's esophagus (BE) is reported to be a precursor that strongly increases the risk of EAC. Due to the complexity of these diseases, their molecular mechanisms have not been revealed clearly. This study aims to explore the gene signatures shared between BE and EAC based on integrated network analysis. We obtained EAC- and BE-associated microarray datasets GSE26886, GSE1420, GSE37200, and GSE37203 from the Gene Expression Omnibus and ArrayExpress using systematic meta-analysis. These data were accompanied by clinical data and RNAseq data from The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis were conducted to explore the relationship between gene sets and clinical traits as well as to discover the key relationships behind the co-expression modules. A differentially expressed gene-based protein–protein interaction (PPI) complex was used to extract hub genes through Cytoscape plugins. As a result, 403 DEGs were excavated, comprising 236 upregulated and 167 downregulated genes, which are involved in the cell cycle and replication pathways. Forty key genes were identified using modules of MCODE, CytoHubba, and CytoNCA with different algorithms. A dark-gray module with 207 genes was identified which having a high correlation with phenotype (gender) in the WGCNA. Furthermore, five shared hub gene signatures (SHGS), namely, pre-mRNA processing factor 4 (PRPF4), serine and arginine-rich splicing factor 1 (SRSF1), heterogeneous nuclear ribonucleoprotein M (HNRNPM), DExH-Box Helicase 9 (DHX9), and origin recognition complex subunit 2 (ORC2), were identified between BE and EAC. SHGS enrichment denotes that RNA metabolism and splicosomes play a key role in esophageal cancer development and progress. We conclude that the PPI complex and WGCNA co-expression network highlight the importance of phenotypic identifying hub gene signatures for BE and EAC.
Highlights
Esophageal cancer is a deadly cancer considering its high mortality rate, with 572,034 newly diagnosed cases and 508,585 deaths in 2018 (Bray et al, 2018)
The results of microarray dataset-based PPI networks and WGCNA exhibited that the dark-gray module had the maximum association with esophageal adenocarcinoma (EAC) and Barrett's esophagus (BE), with the identification of five SHGS, namely pre-mRNA processing factor 4 (PRPF4), serine and arginine rich splicing factor 1 (SRSF1), heterogeneous nuclear ribonucleoprotein M (HNRNPM), DExHbox helicase 9 (DHX9), and origin recognition complex subunit 2 (ORC2)
The WGCNA-based gene co-expression network indicated that the relationships between co-expressed genes and clinical trait were associated with the progression of esophageal cancer
Summary
Esophageal cancer is a deadly cancer considering its high mortality rate, with 572,034 newly diagnosed cases and 508,585 deaths in 2018 (Bray et al, 2018). Esophageal cancer is classified into two subcategories: esophageal adenocarcinoma (EAC; distal esophagus) and esophageal squamous cell carcinoma (ESCC; proximal esophagus). It starts from the esophageal epithelium, the innermost layer of the esophagus (Rustgi and El-Serag, 2014). According to the geographic variation, EAC is more common in economically advanced regions than in low-income countries (Chai et al, 2019). The common risk factors of EAC are age, male sex, obese, gastroesophageal reflux disease (GERD), cigarette smoking, and diet (low in vegetables and fruits). Surgical therapy has improved the patient's survival yet it is not suitable for advanced-stage cancer patients (Davies et al, 2014)
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