Abstract
BackgroundThe plasminogen activation system plays a pivotal role in regulating tumorigenesis. In this work, we aim to identify key regulators of plasminogen activation associated with tumorigenesis and explore potential mechanisms in gastric cancer (GC).MethodsGene profiling datasets were extracted from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were screened for and obtained by the GEO2R tool. The Database for Annotation, Visualization and Integrated Discovery was used for GO and KEGG enrichment analysis. Gene set enrichment analysis (GSEA) was performed to verify molecular signatures and pathways among The Cancer Genome Atlas or GEO datasets. Correlations between SERPINE1 and markers of epithelial-to-mesenchymal transition (EMT) were analyzed using the GEPIA database and quantitative real-time PCR (qRT-PCR). Interactive networks of selected genes were built by STRING and Cytoscape software. Finally, selected genes were verified with the Kaplan–Meier (KM) plotter database.ResultsA total of 104 overlapped upregulated and 61 downregulated DEGs were obtained. Multiple GO and KEGG terms associated with the extracellular matrix were enriched among the DEGs. SERPINE1 was identified as the only regulator of angiogenesis and the plasminogen activator system among the DEGs. A high level of SERPINE1 was associated with a poor prognosis in GC. GSEA analysis showed a strong correlation between SERPINE1 and EMT, which was also confirmed with the GEPIA database and qRT-PCR validation. FN1, TIMP1, MMP2, and SPARC were correlated with SERPINE1.The KM plotter database showed that an overexpression of these genes correlated with a shorter survival time in GC patients.ConclusionsIn conclusion, SERPINE1 is a potent biomarker associated with EMT and a poor prognosis in GC. Furthermore, FN1, TIMP1, MMP2, and SPARC are correlated with SERPINE1 and may serve as therapeutic targets in reversing EMT in GC.
Highlights
Gastric cancer (GC) is one of the most lethal cancers with tremendous cancer-related mortality (Van Cutsem et al, 2016)
Screening and bioinformatic analysis of differentially expressed genes (DEGs) in Gene Expression Omnibus (GEO) datasets To identify DEGs associated with gastric tumorigenesis, we applied the GEO2R tool to screen for DEGs between normal and tumor tissues
KEGG enrichment analysis showed that extracellular matrix (ECM)-receptor interaction, protein digestion and absorption, PI3K-AKT signaling pathway, gastric acid secretion, and focal adhesion were significantly enriched in DEGs (Fig. 1F), suggesting that alterations of the ECM might be responsible for the malignant progress of gastric cancer (GC)
Summary
Gastric cancer (GC) is one of the most lethal cancers with tremendous cancer-related mortality (Van Cutsem et al, 2016). Plasminogen activator inhibitor-1 (PAI-1), encoded by the Serpin E1 (SERPINE1) gene, is a key regulator of the uPA system. We aim to identify key regulators of plasminogen activation associated with tumorigenesis and explore potential mechanisms in gastric cancer (GC). Gene set enrichment analysis (GSEA) was performed to verify molecular signatures and pathways among The Cancer Genome Atlas or GEO datasets. Multiple GO and KEGG terms associated with the extracellular matrix were enriched among the DEGs. SERPINE1 was identified as the only regulator of angiogenesis and the plasminogen activator system among the DEGs. A high level of SERPINE1 was associated with a poor prognosis in GC. FN1, TIMP1, MMP2, and SPARC were correlated with SERPINE1.The KM plotter database showed that an overexpression of these genes correlated with a shorter survival time in GC patients. FN1, TIMP1, MMP2, and SPARC are correlated with SERPINE1 and may serve as therapeutic targets in reversing EMT in GC
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