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Molecular dysexpression in gastric cancer revealed by integrated analysis of transcriptome data.

ABSTRACT: Gastric cancer (GC) is often diagnosed in the advanced stages and is associated with a poor prognosis. Obtaining an in depth understanding of the molecular mechanisms of GC has lagged behind compared with other cancers. This study aimed to identify candidate biomarkers for GC. An integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between GC and normal tissues. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then performed to identify the functions of the DEGs. Furthermore, a protein-protein interaction (PPI) network of the DEGs was constructed. The expression levels of the DEGs were validated in human GC tissues using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A set of 689 DEGs were identified in GC tissues, as compared with normal tissues, including 202 upregulated DEGs and 487 downregulated DEGs. The KEGG pathway analysis suggested that various pathways may play important roles in the pathology of GC, including pathways related to protein digestion and absorption, extracellular matrix-receptor interaction, and the metabolism of xenobiotics by cytochrome P450. The PPI network analysis indicated that the significant hub proteins consisted of SPP1, TOP2A and ARPC1B. RT-qPCR validation indicated that the expression levels of the top 10 most significantly dysexpressed genes were consistent with the illustration of the integrated analysis. The present study yielded a reference list of reliable DEGs, which represents a robust pool of candidates for further evaluation of GC pathogenesis and treatment.

SUBMITTER: Li X

PROVIDER: S-EPMC5431188 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Molecular dysexpression in gastric cancer revealed by integrated analysis of transcriptome data.

Li Xiaomei X Dong Weiwei W Qu Xueling X Zhao Huixia H Wang Shuo S Hao Yixin Y Li Qiuwen Q Zhu Jianhua J Ye Min M Xiao Wenhua W

Oncology letters 20170303 5

Gastric cancer (GC) is often diagnosed in the advanced stages and is associated with a poor prognosis. Obtaining an in depth understanding of the molecular mechanisms of GC has lagged behind compared with other cancers. This study aimed to identify candidate biomarkers for GC. An integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between GC and normal tissues. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analy ...[more]

PMID: 28521423

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Project description:The biological role and prognostic value of thrombospondin domain-containing 7A (THSD7A) in gastric cancer remain unclear. Our purpose was to determine the molecular mechanisms underlying the functioning of THSD7A and its prognostic value in gastric cancer. Gastric cancer-associated single cell and bulk RNA sequencing data obtained from two databases, were analyzed. We used bulk RNA sequencing to examine the differential expression of THSD7A in gastric cancer and normal gastric tissues and explored the relationship between THSD7A expression and clinicopathological characteristics. Kaplan-Meier survival and Cox analyses revealed the prognostic value of THSD7A. Gene set enrichment and immune infiltration analyses were used to determine the cancer-promoting mechanisms of THSD7A and its effect on the immune microenvironment. We explored the relationship between THSD7A expression and sensitivity of anti-tumor drugs and immune checkpoint levels. Biological functions of THSD7A were validated at single-cell and in vitro levels. THSD7A expression was significantly increased in gastric cancer samples. High THSD7A expression was associated with poor clinical phenotypes and prognoses. Cox analysis showed that THSD7A was an independent risk factor for patients with gastric cancer. Enrichment analysis suggested that epithelial-mesenchymal transition and inflammatory responses may be potential pro-cancer mechanisms of THSD7A. Upregulation of THSD7A promoted infiltration by M2 macrophages and regulatory T cells. High THSD7A expression suppressed the sensitivity of patients with gastric cancer to drugs, such as 5-fluorouracil, bleomycin, and cisplatin, and upregulated immune checkpoints, such as HAVCR2, PDCD1LG2, TIGIT, and CTLA4. At the single cell level, THSD7A was an endothelial cell-associated gene and endothelial cells overexpressing THSD7A showed unique pro-oncogenic effects. In vitro experiments confirmed that THSD7A was overexpressed in gastric cancer samples and cells, and that knocking out THSD7A significantly inhibited gastric cancer cell proliferation and invasion. THSD7A overexpression may be a unique prognostic marker and therapeutic target in gastric cancer. Therefore, our study provides a new perspective on the precise treatment of gastric cancer.

Project description:ObjectiveGastric cancer (GC) is the fourth most common cause of cancer-related deaths in the world. In the current study, we aim to identify the hub genes and uncover the molecular mechanisms of GC.MethodsThe expression profiles of the genes and the miRNAs were extracted from the Gene Expression Omnibus database. The identification of the differentially expressed genes (DEGs), including miRNAs, was performed by the GEO2R. Database for Annotation, Visualization and Integrated Discovery was used to perform GO and KEGG pathway enrichment analysis. The protein-protein interaction (PPI) network and miRNA-gene network were constructed using Cytoscape software. The hub genes were identified by the Molecular Complex Detection (MCODE) plugin, the CytoHubba plugin and miRNA-gene network. Then, the identified genes were verified by Kaplan-Meier plotter database and quantitative real-time PCR (qRT-PCR) in GC tissue samples.ResultsA total of three mRNA expression profiles (GSE13911, GSE79973 and GSE19826) were downloaded from the Gene Expression Omnibus (GEO) database, including 69, 20 and 27cases separately. A total of 120 overlapped upregulated genes and 246 downregulated genes were identified. The majority of the DEGs were enriched in extracellular matrix organization, collagen catabolic process, collagen fibril organization and cell adhesion. In addition, three KEGG pathways were significantly enriched, including ECM-receptor interaction, protein digestion and absorption, and the focal adhesion pathways. In the PPI network, five significant modules were detected, while the genes in the modules were mainly involved in the ECM-receptor interaction and focal adhesion pathways. By combining the results of MCODE, CytoHubba and miRNA-gene network, a total of six hub genes including COL1A2, COL1A1, COL4A1, COL5A2, THBS2 and ITGA5 were chosen. The Kaplan-Meier plotter database confirmed that higher expression levels of these genes were related to lower overall survival, except for COL5A2. Experimental validation showed that the rest of the five genes had the same expression trend as predicted.ConclusionIn conclusion, COL1A2, COL1A1, COL4A1, THBS2 and ITGA5 may be potential biomarkers and therapeutic targets for GC. Moreover, ECM-receptor interaction and focal adhesion pathways play significant roles in the progression of GC.

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Molecular dysexpression in gastric cancer revealed by integrated analysis of transcriptome data.

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Molecular dysexpression in gastric cancer revealed by integrated analysis of transcriptome data.

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