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Identification of genes associated with histologic tumor grade of esophageal squamous cell carcinoma.

ABSTRACT: The present study aimed to identify the genes associated with the histologic tumor grade of patients with esophageal squamous cell carcinoma (ESCC) and to provide valuable information for the identification of potential diagnostic biomarkers in ESCC. Tumor samples of ESCC patients retrieved from The Cancer Genome Atlas were divided into Grade 1 (well-differentiated; G1), Grade 2 (moderately-differentiated; G2) and Grade 3 (poorly-differentiated; G3) groups in accordance with the clinical record of the tumor grade of ESCC patients. The genes associated with tumor grade were identified. The signaling pathways of identified genes were enriched from the Kyoto Encyclopedia of Genes and Genomes (KEGG). The diagnostic value of candidate genes was assessed by receiver operating characteristic analysis. We used the GSE23400 dataset generated from the Gene Expression Omnibus to examine the expression levels of candidate genes in ESCC tissues compared to matched mucosa tissues. In total, 440 genes positively correlated with tumor grade and 882 genes negatively correlated with tumor grade were identified. There were 310 differentially expressed genes (DEGs) between G1 and G2, 184 DEGs between G2 and G3, and 710 DEGs between G1 and G3. There were 1322 genes associated with tumor grade that were significantly enriched in pathways in cancer and the phospholipase D signaling pathway. Cyclin-dependent kinase inhibitor 1A, golgin A7 family member B and transforming growth factor B1-induced anti-apoptotic factor 1 (TIAF1) had potential diagnostic value for discriminating ESCC patients with G1 from those with G3. TIAF1 was significantly down-regulated in ESCC. The results of the present study comprise useful groundwork with respect to determining the tumorigenesis mechanism in ESCC and discovering potential diagnostic biomarkers for ESCC.

SUBMITTER: Xing J

PROVIDER: S-EPMC5586336 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Identification of genes associated with histologic tumor grade of esophageal squamous cell carcinoma.

Xing Jiaqiang J Liu Cuicui C

FEBS open bio 20170728 9

The present study aimed to identify the genes associated with the histologic tumor grade of patients with esophageal squamous cell carcinoma (ESCC) and to provide valuable information for the identification of potential diagnostic biomarkers in ESCC. Tumor samples of ESCC patients retrieved from <i>The Cancer Genome Atlas</i> were divided into Grade 1 (well-differentiated; G1), Grade 2 (moderately-differentiated; G2) and Grade 3 (poorly-differentiated; G3) groups in accordance with the clinical ...[more]

PMID: 28904855

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Project description:Background Esophageal cancer (EC) is a highly aggressive malignancy that is classified as esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Infiltrating stromal/immune cells, a major component of the tumor immune microenvironment (TIME), have prognostic significance in various cancers. Methods In this study we investigated genes and immune factors in the tumor microenvironment (TME) of ESCC and EAC that can serve as prognostic biomarkers. Stromal and immune scores were calculated using the Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data (ESTIMATE) algorithm based on gene expression profiles of patient-derived tumor tissues in The Cancer Genome Atlas database. The correlation between ESTIMATE scores and survival rates in EC were analyzed. A comparison of high and low stromal/immune score groups revealed multiple differentially expressed genes (DEGs) as candidate prognostic genes; their role in immune-related biological processes was evaluated by functional and protein-protein interaction (PPI) network analyses, and the genes were validated using Gene Expression Omnibus datasets. Additionally, 22 tumor-infiltrating immune cell (TIIC) subsets were analyzed using the CIBERSORT algorithm. Results Median stromal score was higher whereas immune score was lower in ESCC than in EAC (both P<0.01). Stromal score was lower in female as compared to male ESCC patients (P<0.05), and was significantly correlated with T stage (P<0.05). In EAC, median immune score was higher in female as compared to male patients (P<0.05) and was correlated with tumor-node-metastasis stage (P<0.05). The identified DEGs were mainly involved in lymphocyte (especially T-lymphocyte) activation and carbohydrate binding. Moreover, the levels of infiltrating resting-stage dendritic cells, CD8+ T cells, naïve B cells, activated mast cells, and resting memory CD4+ T cells were significantly correlated with EC prognosis (P<0.05). Conclusions The immune microenvironment of ESCC and EAC are quite different. We have found genes with prognostic value in multiple tumor databases.

Project description:To uncover the genes associated with the development of esophageal squamous cell carcinoma (ESCC), an ESCC microarray dataset was used to identify genes differentially expressed between ESCC and normal control tissues. The dataset GSE17351 was downloaded from the Gene Expression Omnibus, containing 5 tumor esophageal mucosa samples and 5 adjacent normal esophageal mucosa samples from 5 male patients with ESCC. The differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Data R package. Then, a co-expression network was constructed using the Weighted Correlation Network Analysis (WGCNA) package, and co-expression network modules were obtained with a hierarchical clustering algorithm. Additionally, functional enrichment analyses for DEGs in the top 2 modules with the highest significance were respectively conducted using the WGCNA package and the cluster Profiler package. In total, 487 upregulated and 468 downregulated DEGs were identified. A total of 24 modules were obtained from the co-expression network, and the top 2 modules with the highest significance, designated as 'blue4' and 'magenta', were further analyzed. In the module blue4, DEGs were significantly enriched in a number of Gene Ontology terms, including 'spindle organization' [e.g., ubiquitin conjugating enzyme E2 C (UBE2C) and SAC3 domain containing 1] and 'cell cycle process' [e.g., UBE2C, minichromosome maintenance complex component 6 (MCM6) and cell division cycle 20 (CDC20)]. Furthermore, a number of DEGs (e.g., UBE2C, CDC20 and MCM6) were enriched in the 'cell cycle' and 'ubiquitin mediated proteolysis' pathways. In the module 'magenta', a number of DEGs [e.g., transferrin receptor (TFRC) and TEA domain transcription factor 4 (TEAD4)] were enriched in the primary metabolic process and intracellular membrane-bounded organelle. Additionally, 308 upregulated genes and 215 downregulated genes were differentially expressed in the same pattern in another dataset, GSE20347, including UBE2C, CDC20, MCM6, TFRC, TEAD4, protein phosphatase 1 regulatory subunit 3C and MAL, T-cell differentiation protein. These DEGs may function in the development of ESCC.

Project description:Aberrant methylated genes (DMGs) play an important role in the etiology and pathogenesis of esophageal squamous cell carcinoma (ESCC). In this study, we aimed to integrate three cohorts profile datasets to ascertain aberrant methylated-differentially expressed genes and pathways associated with ESCC by comprehensive bioinformatics analysis. We downloaded data of gene expression microarrays (GSE20347, GSE38129) and gene methylation microarrays (GSE52826) from the Gene Expression Omnibus (GEO) database. Aberrantly differentially expressed genes (DEGs) were obtained by GEO2R tool. The David database was then used to perform Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses on selected genes. STRING and Cytoscape software were used to construct a protein-protein interaction (PPI) network, then the modules in the PPI networks were analyzed with MCODE and the hub genes chose from the PPI networks were verified by Oncomine and TCGA database. In total, 291 hypomethylation-high expression genes and 168 hypermethylation-low expression genes were identified at the screening step, and finally found six mostly changed hub genes including KIF14, CDK1, AURKA, LCN2, TGM1, and DSG1. Pathway analysis indicated that aberrantly methylated DEGs mainly associated with the P13K-AKT signaling, cAMP signaling and cell cycle process. After validation in multiple databases, most hub genes remained significant. Patients with high expression of AURKA were associated with shorter overall survival. To summarize, we have identified six feasible aberrant methylated-differentially expressed genes and pathways in ESCC by bioinformatics analysis, potentially providing valuable information for the molecular mechanisms of ESCC. Our data combined the analysis of gene expression profiling microarrays and gene methylation profiling microarrays, simultaneously, and in this way, it can shed a light for screening and diagnosis of ESCC in future.

Project description:The aim of the present study was to identify the differentially expressed genes (DEGs) in esophageal squamous-cellcarcinoma (ESCC) and provide potential therapeutic targets. The microarray dataset GSE20347 was downloaded from the Gene Expression Omnibus (GEO) database, and included 17 tissue samples and 13 normal adjacent tissue samples from patients with ESCC. A total of 22,277 DEGs were identified. A heat map for the DEGs was constructed with the Morpheus online tool and the top 200 genes (100 upregulated and 100 downregulated) were selected for further bioinformatics analysis, including analysis of gene ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, protein-protein interaction networks and Spearman's correlation tests. The results of the GO analysis indicated that the upregulated DEGs were most significantly enriched in membrane-bounded vesicles in the cellular component (CC) category, but were not significantly enriched in any GO terms of the categories biological process (BP) or molecular function (MF); furthermore, the downregulated DEGs were most significantly enriched in regulation of DNA metabolic processes, nucleotide binding and chromosomes in the categories BP, MF and CC, respectively. The KEGG analysis indicated that the downregulated DEGs were enriched in the regulation of cell cycle pathways. The top 10 hub proteins in the protein-protein interaction network were cyclin-dependent kinase 4, budding uninhibited by benzimidazoles 1, cyclin B2, heat shock protein 90AA1, aurora kinase A, H2A histone family member Z, replication factor C subunit 4, and minichromosome maintenance complex component 2, -4 and -7. These proteins are mainly involved in regulating tumor progression. The genes in the four top modules were mainly implicated in regulating cell cycle pathways. Secreted Ly-6/uPAR-related protein (SLURP) was the hub gene, and SLURP and its interacting genes were most enriched in the chromosomal part in the CC category, organelle organization in the BP category and protein binding in the MF category, and were involved in pathways including DNA replication, cell cycle and P53 signaling. The expression of SLURP-1 in fifteen patients with esophageal carcinoma was detected using quantitative polymerase chain reaction analysis, and the results indicated that SLURP-1 expression was significantly decreased in the tumor samples relative to that in normal adjacent tissues. These results suggest that several hub proteins and the hub gene SLURP-1 may serve as potential therapeutic targets, and that gene dysfunction may be involved in the tumorigenesis of ESCC.

Project description:BackgroundEstrogen therapy has positively impact the treatment of several cancers, such as prostate, lung and breast cancers. Moreover, several groups have reported the importance of estrogen induced gene regulation in esophageal cancer (EC). This suggests that there could be a potential for estrogen therapy for EC. The efficient design of estrogen therapies requires as complete as possible list of genes responsive to estrogen. Our study develops a systems biology methodology using esophageal squamous cell carcinoma (ESCC) as a model to identify estrogen responsive genes. These genes, on the other hand, could be affected by estrogen therapy in ESCC.ResultsBased on different sources of information we identified 418 genes implicated in ESCC. Putative estrogen responsive elements (EREs) mapped to the promoter region of the ESCC genes were used to initially identify candidate estrogen responsive genes. EREs mapped to the promoter sequence of 30.62% (128/418) of ESCC genes of which 43.75% (56/128) are known to be estrogen responsive, while 56.25% (72/128) are new candidate estrogen responsive genes. EREs did not map to 290 ESCC genes. Of these 290 genes, 50.34% (146/290) are known to be estrogen responsive. By analyzing transcription factor binding sites (TFBSs) in the promoters of the 202 (56+146) known estrogen responsive ESCC genes under study, we found that their regulatory potential may be characterized by 44 significantly over-represented co-localized TFBSs (cTFBSs). We were able to map these cTFBSs to promoters of 32 of the 72 new candidate estrogen responsive ESCC genes, thereby increasing confidence that these 32 ESCC genes are responsive to estrogen since their promoters contain both: a/mapped EREs, and b/at least four cTFBSs characteristic of ESCC genes that are responsive to estrogen. Recent publications confirm that 47% (15/32) of these 32 predicted genes are indeed responsive to estrogen.ConclusionTo the best of our knowledge our study is the first to use a cancer disease model as the framework to identify hormone responsive genes. Although we used ESCC as the disease model and estrogen as the hormone, the methodology can be extended analogously to other diseases as the model and other hormones. We believe that our results provide useful information for those interested in genes responsive to hormones and in the design of hormone-based therapies.

Dataset Information

Identification of genes associated with histologic tumor grade of esophageal squamous cell carcinoma.

Publications

Identification of genes associated with histologic tumor grade of esophageal squamous cell carcinoma.

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