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Identification of hub genes, key miRNAs and potential molecular mechanisms of colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) is the most common cancer of the digestive system. The aim of the present study was to identify the potential biomarkers and uncover the underlying mechanisms. The gene and miRNA expression profiles were obtained from GEO database. The differentially expressed genes (DEGs) and miRNAs (DE miRNAs) were identified by GEO2R. The gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by KOBAS 3.0. The protein-protein interaction (PPI) network and miRNA-gene network were constructed by Cytoscape software. Then, the identified genes were verified by quantitative real-time PCR in both CRC tissue samples and cell lines. A total of 600 upregulated DEGs, 283 downregulated DEGs, 13 upregulated DE miRNAs and 7 downregulated DE miRNAs were identified. GO analysis results showed that upregulated DEGs were significantly enriched in binding, organelle and cellular process. Downregulated DEGs were enriched in binding, extracellular region and chemical homeostasis. KEGG analysis showed that the DEGs were mostly enriched in cell cycle and pathways in cancer. A total of eight genes were identified as biomarkers, including CAD, ITGA2, E2F3, BCL2, PRKACB, IGF1, SGK1 and NR3C1. Experimental validation showed that seven of the eight identified genes had the same expression trend as predicted, except for ITGA2. Besides, hsa-miR-552 and hsa?miR-30a were identified as key miRNAs. the present study provides a series of biomarkers and mechanisms for the diagnosis and therapy of CRC. We also prove that although bioinformatics analysis is a wonderful approach, experiment validation is necessary.

SUBMITTER: Wu S

PROVIDER: S-EPMC5652954 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Identification of hub genes, key miRNAs and potential molecular mechanisms of colorectal cancer.

Wu Shasha S Wu Feixiang F Jiang Zheng Z

Oncology reports 20170829 4

Colorectal cancer (CRC) is the most common cancer of the digestive system. The aim of the present study was to identify the potential biomarkers and uncover the underlying mechanisms. The gene and miRNA expression profiles were obtained from GEO database. The differentially expressed genes (DEGs) and miRNAs (DE miRNAs) were identified by GEO2R. The gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by KOBAS 3.0. The protein-protein in ...[more]

PMID: 28902367

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Project description:Objective:Gastric 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. Methods:The 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. Results:A 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. Conclusion:In 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.

Project description:Colorectal cancer (CRC) is the most common malignant gastrointestinal tumor worldwide. Serum exosomal microRNAs (miRNAs) play a critical role in tumor progression and metastasis. However, the underlying molecular mechanisms are poorly understood.The miRNAs expression profile (GSE39833) was downloaded from Gene Expression Omnibus (GEO) database. GEO2R was applied to screen the differentially expressed miRNAs (DEmiRNAs) between healthy and CRC serum exosome samples. The target genes of DEmiRNAs were predicted by starBase v3.0 online tool. The gene ontology (GO) and Kyoto Encyclopedia of Genomes pathway (KEGG) enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. The protein-protein interaction (PPI) network was established by the Search Tool for the Retrieval of Interacting Genes (STRING) visualized using Cytoscape software. Molecular Complex Detection (MCODE) and cytohubba plug-in were used to screen hub genes and gene modules.In total, 102 DEmiRNAs were identified including 67 upregulated and 35 downregulated DEmiRNAs, and 1437 target genes were predicted. GO analysis showed target genes of upregulated DEmiRNAs were significantly enriched in transcription regulation, protein binding, and ubiquitin protein ligase activity. While the target genes of downregulated DEmiRNAs were mainly involved in transcription from RNA polymerase II promoter, SMAD binding, and DNA binding. The KEGG pathway enrichment analyses showed target genes of upregulated DEmiRNAs were significantly enriched in proteoglycans in cancer, microRNAs in cancer, and phosphatidylinositol-3 kinases/Akt (PI3K-Akt) signaling pathway, while target genes of downregulated DEmiRNAs were mainly enriched in transforming growth factor-beta (TGF-beta) signaling pathway and proteoglycans in cancer. The genes of the top 3 modules were mainly enriched in ubiquitin mediated proteolysis, spliceosome, and mRNA surveillance pathway. According to the cytohubba plugin, 37 hub genes were selected, and 4 hub genes including phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), SRC, cell division cycle 42 (CDC42), E1A binding protein p300 (EP300) were identified by combining 8 ranked methods of cytohubba.The study provides a comprehensive analysis of exosomal DEmiRNAs and target genes regulatory network in CRC, which can better understand the roles of exosomal miRNAs in the development of CRC. However, these findings require further experimental validation in future studies.

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Dataset Information

Identification of hub genes, key miRNAs and potential molecular mechanisms of colorectal cancer.

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Identification of hub genes, key miRNAs and potential molecular mechanisms of colorectal cancer.

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