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Identification of the key transcription factors in esophageal squamous cell carcinoma.

ABSTRACT: Background:Esophageal cancer (EC) is a common human malignancy worldwide. Esophageal squamous cell carcinoma (ESCC) is the predominant subtype in China. The tumorigenesis mechanism in ESCC is unclear. The aim of this study was to identify key transcription factors (TFs) in ESCC and elucidate the mechanism of it. Methods:A total of ten published microarray datasets of ESCC was downloaded from the Gene Expression Omnibus (GEO). Then, bioinformatics analyses including differentially expressed genes (DEGs) analysis, gene ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, TFs-genes regulatory network construction was performed. Quantitative real-time polymerase chain reactions (qRT-PCR) were used to detect the expression levels of TFs and DEGs in ESCC. The association between stage and TFs and the association between survival and TFs were evaluated based on The Cancer Genome Atlas (TCGA), respectively. Results:A total of 1,248 dysregulated genes were selected as DEGs in ESCC. A total of 26 TFs and corresponding target-genes were identified. The ESCC-specific transcriptional regulatory network was constructed. The network was consisted of 882 edges and 631 nodes. BRCA1, SOX10, ARID3A, ZNF354C and NFIC had the highest connectivity with DEGs, and regulated 92, 89, 82, 79 and 78 DEGs in the network, respectively. All these 1,248 DEGs were significantly enriched in cell cycle, DNA replication and oocyte meiosis pathways. The qRT-PCR results were consistent with our microarray analysis. High expression of SREBF1 and TFAP2A were significantly correlated with the longer overall survival time of patients with ESCC. Conclusions:BRCA1, SOX10, ARID3A, ZNF354C and NFIC might be the key TFs in carcinogenesis and development of ESCC by regulating their corresponding target-genes involved in cell cycle, DNA replication and oocyte meiosis pathways. SREBF1 and TFAP2A may be two potential prognostic biomarkers of ESCC.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5863113 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Identification of the key transcription factors in esophageal squamous cell carcinoma.

Zhang Yuefeng Y Xu Yanzhao Y Li Zhenhua Z Zhu Yonggang Y Wen Shiwang S Wang Mingbo M Lv Huilai H Zhang Fan F Tian Ziqiang Z

Journal of thoracic disease 20180101 1

<h4>Background</h4>Esophageal cancer (EC) is a common human malignancy worldwide. Esophageal squamous cell carcinoma (ESCC) is the predominant subtype in China. The tumorigenesis mechanism in ESCC is unclear. The aim of this study was to identify key transcription factors (TFs) in ESCC and elucidate the mechanism of it.<h4>Methods</h4>A total of ten published microarray datasets of ESCC was downloaded from the Gene Expression Omnibus (GEO). Then, bioinformatics analyses including differentially ...[more]

PMID: 29600044

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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:Background: Esophageal cancer (EC) is one of the deadliest cancers in the world. However, the mechanism that drives the evolution of EC is still unclear. On this basis, we identified the key genes and molecular pathways that may be related to the progression of esophageal adenocarcinoma and squamous cell carcinoma to find potential markers or therapeutic targets. Methods: GSE26886 were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) among normal samples, EA, and squamous cell carcinoma were determined using R software. Then, potential functions of DEGs were determined using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The STRING software was used to identify the most important modules in the protein-protein interaction (PPI) network. The expression levels of hub genes were confirmed using UALCAN database. Kaplan-Meier plotters were used to confirm the correlation between hub genes and outcomes in EC. Results: In this study, we identified 1,098 genes induced in esophageal adenocarcinoma (EA) and esophageal squamous cell carcinoma (ESCC), and 669 genes were reduced in EA and ESCC, suggesting that these genes may play an important role in the occurrence and development of EC tumors. Bioinformatics analysis showed that these genes were involved in cell cycle regulation and p53 and phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. In addition, we identified 147 induced genes and 130 reduced genes differentially expressed in EA and ESCC. The expression of ESCC in the EA group was different from that in the control group. By PPI network analysis, we identified 10 hub genes, including GNAQ, RGS5, MAPK1, ATP1B1, HADHA, HSDL2, SLC25A20, ACOX1, SCP2, and NLN. TCGA validation showed that these genes were present in the dysfunctional samples between EC and normal samples and between EA and ESCC. Kaplan-Meier analysis showed that MAPK1, ACOX1, SCP2, and NLN were associated with overall survival in patients with ESCC and EA. Conclusions: In this study, we identified a series of DEGs between EC and normal samples and between EA and ESCC samples. We also identified 10 key genes involved in the EC process. We believe that this study may provide a new biomarker for the prognosis of EA and ESCC.

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Identification of the key transcription factors in esophageal squamous cell carcinoma.

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Identification of the key transcription factors in esophageal squamous cell carcinoma.

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