Abstract
Gastric cancer (GC) is the second most frequent cause of cancer-related deaths worldwide. MicroRNAs are single-stranded RNA molecules of 21–23 nucleotides that regulate target gene expression through specific base-pairing interactions between miRNA and untranslated regions of targeted mRNAs. In this study, we generated a multistep approach for the integrated analysis of miRNA and mRNA expression. First, both miRNA and mRNA expression profiling datasets in gastric cancer from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) identified 79 and 1042 differentially expressed miRNAs and mRNAs, respectively, in gastric cancer. Second, inverse correlations between miRNA and mRNA expression levels identified 3206 miRNA–mRNA pairs combined with 79 dysregulated miRNAs and their 774 target mRNAs predicted by three prediction tools, miRanda, PITA, and RNAhybrid. Additionally, miR-204, which was found to be down-regulated in gastric cancer, was ectopically over-expressed in the AGS gastric cancer cell line and all down-regulated targets were identified by RNA sequencing (RNA-seq) analysis. Over-expression of miR-204 reduced the gastric cancer cell proliferation and suppressed the expression of three targets which were validated by qRT-PCR and luciferase assays. For the first time, we identified that CKS1B, CXCL1, and GPRC5A are putative targets of miR-204 and elucidated that miR-204 acted as potential tumor suppressor and, therefore, are useful as a promising therapeutic target for gastric cancer.
Highlights
Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide [1]
Namely CD55, CKS1B, CXCL1, GPRC5A and TNS4, with significant gene ontology terms such as regulation of cell cycle, cell proliferation, cell death, cell cycle, programmed cell death, regulation of apoptosis, anti-apoptosis, signal transduction and immune response were selected for further experimental validation
Many studies showed that miRNAs play critical roles in causing tumorigenesis of gastric cancer and have clinical significance in prognosis, diagnosis and treatment [22,23,24]
Summary
Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide [1]. MiRNAs are involved in different cellular processes like metabolism, differentiation, development and apoptosis and can regulate both oncogenes and tumor suppressor genes [7]. Many studies have shown the dysregulation of miRNAs in gastric cancer, such a multistep approach for an integrated analysis has yet to be carried out to identify important miRNA and their targets as biomarkers in gastric cancer. Among the down-regulated miRNAs, miR-204 was selected for ectopic over-expression in the AGS gastric cancer cell line. MiR-204 was ectopically over -expressed in AGS cells which were analyzed by subsequent RNA sequencing (RNA-seq) and all the down-regulated targets of miR-204 were identified. Gene ontology analysis revealed that miRNA-regulated genes have a potential role in biological processes such as regulation of cell cycle, regulation of apoptosis, programmed cell death, acute inflammatory response, regulation of cell proliferation and signal transduction
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