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Identification of the key miRNAs associated with survival time in stomach adenocarcinoma.

ABSTRACT: Stomach adenocarcinoma (STAD) is one of the leading causes of cancer morbidity and mortality worldwide. The present study aimed to identify the microRNAs associated with STAD survival time. The clinical information and microarray miRNA and mRNA expression profiles of STAD patients were downloaded from The Cancer Genome Atlas. Differential expression (DE) analysis was performed to identify DEmiRNAs and DEmRNAs in STAD. The DEmiRNAs associated with the survival time of patients with STAD were identified through DE analysis, negative correlation pair analysis, miRNA target gene prediction, univariate Cox regression analysis and Kaplan-Meier analysis. The functions of the target genes of the DEmiRNAs were predicted with Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A total of 355 DEmiRNAs and 1,722 DEmRNAs were identified between STAD and normal tissues. A total of 5 DEmiRNAs were identified to be associated with STAD survival, including 4 risk-associated DEmiRNAs (miR-30a, -143, -145 and -133b) and 1 protective DEmiRNA (miR-135b). The target DEmRNAs were significantly enriched for DNA metabolic process in the biological process GO category, and in KEGG cell cycle signaling pathways. Kaplan-Meier curves indicated that the overall survival time in the miR-30a, -143, -145 and -133b high expression groups was significantly shorter than that in the low expression groups, whereas the survival time was prolonged in the miR-135b high expression group compared with that in the low expression group. Therefore, miR-30a, -143, -145, -133b and -135b may be involved in the tumorigenesis and development of STAD, and may be potential biomarkers for its early diagnosis and prognosis.

SUBMITTER: Liang L

PROVIDER: S-EPMC5649651 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Identification of the key miRNAs associated with survival time in stomach adenocarcinoma.

Liang Li L Zhang Lingling L Cui Dejun D Yang Daping D

Oncology letters 20170823 4

Stomach adenocarcinoma (STAD) is one of the leading causes of cancer morbidity and mortality worldwide. The present study aimed to identify the microRNAs associated with STAD survival time. The clinical information and microarray miRNA and mRNA expression profiles of STAD patients were downloaded from The Cancer Genome Atlas. Differential expression (DE) analysis was performed to identify DEmiRNAs and DEmRNAs in STAD. The DEmiRNAs associated with the survival time of patients with STAD were iden ...[more]

PMID: 29085454

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Project description:BackgroundLung adenocarcinoma (LUAD) is one of the most common cancers worldwide. The etiology and pathophysiology of LUAD remain unclear. The aim of the present study was to identify the key genes, miRNAs and transcription factors (TFs) associated with the pathogenesis and prognosis of LUAD.MethodsThree gene expression profiles (GSE43458, GSE32863, GSE74706) of LUAD were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by GEO2R.The Gene Ontology (GO) terms, pathways, and protein-protein interactions (PPIs) of these DEGs were analyzed. Bases on DEGs, the miRNAs and TFs were predicted. Furthermore, TF-gene-miRNA co-expression network was constructed to identify key genes, miRNAs and TFs by bioinformatic methods. The expressions and prognostic values of key genes, miRNAs and TFs were carried out through The Cancer Genome Atlas (TCGA) database and Kaplan Meier-plotter (KM) online dataset.ResultsA total of 337 overlapped DEGs (75 upregulated and 262 downregulated) of LUAD were identified from the three GSE datasets. Moreover, 851 miRNAs and 29 TFs were identified to be associated with these DEGs. In total, 10 hub genes, 10 key miRNAs and 10 key TFs were located in the central hub of the TF-gene-miRNA co-expression network, and validated using The Cancer Genome Atlas (TCGA) database. Specifically, seven genes (PHACTR2, MSRB3, GHR, PLSCR4, EPB41L2, NPNT, FBXO32), two miRNAs (hsa-let-7e-5p, hsa-miR-17-5p) and four TFs (STAT6, E2F1, ETS1, JUN) were identified to be associated with prognosis of LUAD, which have significantly different expressions between LUAD and normal lung tissue. Additionally, the miRNA/gene co-expression analysis also revealed that hsa-miR-17-5p and PLSCR4 have a significant negative co-expression relationship (r=?0.33, P=1.67e-14) in LUAD.ConclusionsOur study constructed a regulatory network of TF-gene-miRNA in LUAD, which may provide new insights about the interaction between genes, miRNAs and TFs in the pathogenesis of LUAD, and identify potential biomarkers or therapeutic targets for LUAD.

Project description:ObjectiveGastric carcinoma (GC) is the fifth most commonly diagnosed cancer and the third leading cause of cancer-related deaths globally. The tumor microenvironment plays a significant role in the pathogenesis, prognosis, and response to immunotherapy. However, the immune-related molecular mechanisms underlying GC remain elusive. Bioinformatics analysis of the gene expression of GC and paracancerous healthy tissues from the same patient was performed to identify the key genes and signaling pathways, as well as their correlation to the infiltration of the tumor microenvironment (TME) by various immune cells related to GC development.MethodsWe employed GSE19826, a gene expression profile from the Gene Expression Omnibus (GEO), for our analysis. Functional enrichment analysis of Differentially Expressed Genes (DEGs) was conducted using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database.ResultsCytoscape software facilitated the identification of nine hub DEGs, namely, FN1, COL1A1, COL1A2, THBS2, COL3A1, COL5A1, APOE, SPP1, and BGN. Various network analysis algorithms were applied to determine their high connectivity. Among these hub genes, FN1, COL1A2, THBS2, COL3A1, COL5A1, and BGN were found to be associated with a poor prognosis for GC patients. Subsequent analysis using the TIMER database revealed the infiltration status of the TME concerning the overexpression of these six genes. Specifically, the abovementioned genes demonstrated direct correlations with cancer-associated fibroblasts, M1 and M2 macrophages, myeloid-derived suppressor cells, and activated dendritic cells.ConclusionOur findings suggest that the identified hub genes, particularly BGN, FN1, COL1A2, THBS2, COL3A1, and COL5A1, play crucial roles in GC prognosis and TME cell infiltration. This comprehensive analysis enhances our understanding of the molecular mechanisms underlying GC development and may contribute to the identification of potential therapeutic targets and prognostic markers for GC patients.

Project description:Purpose:Stomach adenocarcinoma (STAD) is one of the most frequently diagnosed cancer in the world with both high mortality and high metastatic capacity. Therefore, the present study aimed to investigate novel therapeutic targets and prognostic biomarkers that can be used for STAD treatment. Materials and Methods:We acquired four original gene chip profiles, namely GSE13911, GSE19826, GSE54129, and GSE65801 from the Gene Expression Omnibus (GEO). The datasets included a total of 114 STAD tissues and 110 adjacent normal tissues. The GEO2R online tool and Venn diagram software were used to discriminate differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) enriched pathways were also performed for annotation and visualization with DEGs. The STRING online database was used to identify the functional interactions of DEGs. Subsequently, we selected the most significant DEGs to construct the protein-protein interaction (PPI) network and to reveal the core genes involved. Finally, the Kaplan-Meier Plotter online database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to analyze the prognostic information of the core DEGs. Results:A total of 114 DEGs (35 upregulated and 79 downregulated) were identified, which were abnormally expressed in the GEO datasets. GO analysis demonstrated that the majority of the upregulated DEGs were significantly enriched in collagen trimer, cell adhesion, and identical protein binding. The downregulated DEGs were involved in extracellular space, digestion, and inward rectifier potassium channel activity. Signaling pathway analysis indicated that upregulated DEGs were mainly enriched in receptor interaction, whereas downregulated DEGs were involved in gastric acid secretion. A total of 80 DEGs were screened into the PPI network complex, and one of the most important modules with a high degree was detected. Furthermore, 10 core genes were identified, namely COL1A1, COL1A2, FN1, COL5A2, BGN, COL6A3, COL12A1, THBS2, CDH11, and SERPINH1. Finally, the results of the prognostic information further demonstrated that all 10 core genes exhibited significantly higher expression in STAD tissues compared with that noted in normal tissues. Conclusion:The multiple molecular mechanisms of these novel core genes in STAD are worthy of further investigation and may reveal novel therapeutic targets and biomarkers for STAD treatment.

Project description:Objective This study was conducted in order to gain a better understanding of the molecular mechanisms of stomach adenocarcinoma (STAD), which is necessary to predict the prognosis of STAD and develop novel gene therapy strategies. Methods In this study, the gene expression profile of GSE118916 in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) was used to explore the differential co-expression genes of STAD and normal tissues. Results A total of 407 STAD samples were collected, consisting of 375 from stomach adenocarcinoma tissues and 32 from normal tissues, as well as RNA-seq count data for 19,600 genes. Forty-two differentially expressed genes were screened by weighted gene co-expression network analysis (WGCNA) and differentially expressed gene analysis. According to the functional annotation analysis of the clusterProfiler R package, these genes were analyzed for GO function enrichment, digestion (biological process), tube bottom material membrane (cell component), and oxidoreductase activity (molecular function). The KEGG pathway was enriched in gastric acid secretion and chemical carcinogenesis. In addition, Cytoscape’s cytoHubba plug-in was used to identify seven hub genes (EWSR1, ESR1, CLTC, PCMT1, TP53, HUWE1, and HDAC1) in a protein–protein interaction (PPI) network consisting of 7 nodes and 11 edges. Compared with normal tissues, CLTC and TP53 genes were upregulated in stomach adenocarcinoma (P < 0.05). TP53 was expressed differently in stages II and IV, EWSR1 was expressed differently in stages II and III, and ESR1 was expressed differently in stages I–III. Among the seven hub genes, Kaplan–Meier analysis and TCGG showed that the expression levels of HDAC1 and CLTC were significantly correlated with OS in patients with stomach adenocarcinoma (P < 0.05). GEPIA2 analysis showed that ESR1 expression was closely correlated with OS and DFS in gastric adenocarcinoma (P < 0.05). Then, the expression of the genes and their correlations were revealed by the R2 Platform (http://r2.amc.nl). Finally, we collected 18 pairs of gastric mucosal tissues from normal people and cancer tissues from patients with stomach adenocarcinoma. The expression levels of the above seven hub genes and their relative protein expression were detected by RT-PCR and immunohistochemistry (IHC). The results showed that the gene and protein expression levels in stomach adenocarcinoma tissues were increased than those in the normal group. Conclusion In summary, we believe that the identified hub genes were related to the occurrence of stomach adenocarcinoma, especially the expression of ESR1, HDAC1, and CLTC genes, which are related to the prognosis and overall survival of patients and may become the potential for the future diagnosis and treatment of STAD.

Dataset Information

Identification of the key miRNAs associated with survival time in stomach adenocarcinoma.

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Identification of the key miRNAs associated with survival time in stomach adenocarcinoma.

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