Abstract
BackgroundGastric cancer (GC), a common malignancy of the human digestive system, represents the second leading cause of cancer-related deaths worldwide. Early detection of GC has a significant impact on clinical outcomes. The aim of this study was to identify potential GC biomarkers.MethodsIn this study, we conducted a multi-step analysis of expression profiles in GC clinical samples downloaded from TCGA database to identify differentially expressed miRNAs (DEMs) and differentially expressed mRNAs (DEGs). Potential prognostic biomarkers from the available DEMs were then established using the Cox regression method. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the biological role of the predicted target genes of the miRNA biomarkers. Then, the prognostic DEM-mediated regulatory network was constructed based on transcription factor (TF)–miRNA–target interaction. Subsequently, the consensus genes were further determined based on the overlap between DEGs and these target genes of DEMs. Besides, expression profile, co-expression analysis, immunity, and prognostic values of these prognostic genes were also investigated to further explore the roles in the mechanism of GC tumorigenesis.ResultsWe got five miRNAs, including miR-23b, miR-100, miR-143, miR-145, and miR-409, which are associated with the overall survival of GC patients. Subsequently, enrichment analysis of the target genes of the miRNA biomarkers shown that the GO biological process terms were mainly enriched in mRNA catabolic process, nuclear chromatin, and RNA binding. In addition, the KEGG pathways were significantly enriched in fatty acid metabolism, extracellular matrix (ECM) receptor interaction, and proteoglycans in cancer pathways. The transcriptional regulatory network consisting of 68 TFs, 4 DEMs, and 58 targets was constructed based on the interaction of TFs, miRNAs, and targets. The downstream gene ETS1 of miR-23b and TCF4 regulated by ETS1 were obtained by the regulatory network construction and co-expression analysis. High expression of ETS1 and TCF4 indicated poor prognosis in GC patients, particularly in the advanced stages. The expression of ETS1 and TCF4 was correlated with CD4+ T cells, CD8+ T cells, and B cells.ConclusionsmiR-23b, ETS1, and TCF4 were identified as the prognostic biomarkers. ETS1 and TCF4 had potential immune function in GC, which provided a theoretical basis for molecular-targeted combined immunotherapy in the future.
Highlights
Gastric cancer (GC), a common malignancy of the human digestive system, represents the second leading cause of cancer-related deaths worldwide
Identification of five differentially expressed miRNAs (DEMs) associated with Overall survival (OS) in stomach adenocarcinoma (STAD) A total of 126 DEMs were obtained after analyzing miRNA expression profiles from The Cancer Genome Atlas (TCGA) with R language using adjusted P value < 0.05 and |log2FC| > 1 as screening criteria
The results showed that the expression of ETS1 and Transcription factor 4 (TCF4) in STAD tissues was positively correlated with the abundance of B cells, CD8+ T cells, and CD4+ T cells and negatively correlated with the abundance of C D4+ memory resting T cells and CD4+ Th1
Summary
Gastric cancer (GC), a common malignancy of the human digestive system, represents the second leading cause of cancer-related deaths worldwide. Gastric cancer (GC) is a common malignancy of the human digestive system and represents the second leading cause of cancer-related deaths worldwide [1]. More and more evidence indicate that miRNAs play an important role in regulating genes associated with malignant biological behavior in cancer cells [5]. MiRNAs combine the untranslated region (UTR) of the messenger RNAs (mRNAs) of their cognate target genes [6]. MiRNAs as oncogenes (onco-miRNAs) or tumor suppressors (tsmiRNAs) by inhibiting the expression of target genes via cleaving the mRNA molecules or inhibiting their translation, suggests their potential as diagnostic markers of malignancy [7, 8]
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