Identification of candidate aberrantly methylated and differentially expressed genes in Esophageal squamous cell carcinoma

Abstract

Aberrant methylated genes (DMGs) play an important role in the etiology and pathogenesis of esophageal squamous cell carcinoma (ESCC). In this study, we aimed to integrate three cohorts profile datasets to ascertain aberrant methylated-differentially expressed genes and pathways associated with ESCC by comprehensive bioinformatics analysis. We downloaded data of gene expression microarrays (GSE20347, GSE38129) and gene methylation microarrays (GSE52826) from the Gene Expression Omnibus (GEO) database. Aberrantly differentially expressed genes (DEGs) were obtained by GEO2R tool. The David database was then used to perform Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses on selected genes. STRING and Cytoscape software were used to construct a protein-protein interaction (PPI) network, then the modules in the PPI networks were analyzed with MCODE and the hub genes chose from the PPI networks were verified by Oncomine and TCGA database. In total, 291 hypomethylation-high expression genes and 168 hypermethylation-low expression genes were identified at the screening step, and finally found six mostly changed hub genes including KIF14, CDK1, AURKA, LCN2, TGM1, and DSG1. Pathway analysis indicated that aberrantly methylated DEGs mainly associated with the P13K-AKT signaling, cAMP signaling and cell cycle process. After validation in multiple databases, most hub genes remained significant. Patients with high expression of AURKA were associated with shorter overall survival. To summarize, we have identified six feasible aberrant methylated-differentially expressed genes and pathways in ESCC by bioinformatics analysis, potentially providing valuable information for the molecular mechanisms of ESCC. Our data combined the analysis of gene expression profiling microarrays and gene methylation profiling microarrays, simultaneously, and in this way, it can shed a light for screening and diagnosis of ESCC in future. Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide, with incidence rates ranking fourth and eighth in China and worldwide, respectively 1,2. ESCC is a serious threat to human health, and its five-year survival rate is less than 10%, making it a leading cause of cancer-related death 3. So far,

LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) silence reduces the proliferation, invasion, migration and angiogenesis in esophageal squamous cell carcinoma via KIF14 (kinesin family member 14)

“…As a member of LETM1-binding genes, kinesin family member 14 (KIF14), a potential oncogene, exhibited promotive effects on the malignant development of many cancers, including gastric cancer [8], colorectal cancer [9] and glioma [10]. Previous studies have verified that KIF14 was overexpressed in ESCC [11,12]. Therefore, it is meaningful to investigate LETM1 and KIF14 together.…”

Dysregulation of KIF14 regulates the cell cycle and predicts poor prognosis in cervical cancer: a study based on integrated approaches

“…In addition, all aforementioned cell cycle markers are involved in tumorigenesis ( 32 - 36 ). Additionally, abnormal expression of KIF14 is often accompanied by abnormal expression of BUB1, TTK, PLK1, CREBBP, and CDK1 and affects the prognosis of several types of cancer (e.g., esophageal squamous cell carcinoma, glioblastoma, retinoblastoma, multiple myeloma, and acute myeloid leukemia) ( 37 - 39 ). Chen et al ( 40 ) found the overexpressed genes (BUB1, BUB1B, TTK, and KIF14) in gastric cancer, which are important parameters included in the nomogram to predict the probability of relapse for gastric cancer patients.…”

MAL suppresses OSCC tumorigenesis by maintaining epithelial cell differentiation

“…Loss of desmosome proteins will promote the process of epithelial-mesenchymal transition (EMT) 22 . As a member of this family, the decreased expression of DSG1 has been reported to be closely related to the occurrence of tumors and poor prognosis in a variety of tumors, including lung cancer, esophageal squamous cell carcinoma, extrahepatic cholangiocarcinoma, anal carcinoma, etc [22][23][24][25] . The studies in OSCC also suggested that the abnormal decrease of DSG1 leads to the loss of intercellular connectivity, thus promoting tumor progression 26,27 .…”