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Bioinformatics Analysis of Key Genes and circRNA-miRNA-mRNA Regulatory Network in Gastric Cancer.

ABSTRACT: Gastric cancer (GC) is one of the most common malignancies in the world, with morbidity and mortality ranking second among all cancers. Accumulating evidences indicate that circular RNAs (circRNAs) are closely correlated with tumorigenesis. However, the mechanisms of circRNAs still remain unclear. This study is aimed at determining hub genes and circRNAs and analyzing their potential biological functions in GC. Expression profiles of mRNAs and circRNAs were downloaded from the Gene Expression Omnibus (GEO) data sets of GC and paracancer tissues. Differentially expressed genes (DEGs) and differentially expressed circRNAs (DE-circRNAs) were identified. The target miRNAs of DE-circRNAs and the bidirectional interaction between target miRNAs and DEGs were predicted. Functional analysis was performed, and the protein-protein interaction (PPI) network and the circRNA-miRNA-mRNA network were established. A total of 456 DEGs and 2 DE-circRNAs were identified with 3 mRNA expression profiles and 2 circRNA expression profiles. GO analysis indicated that DEGs were mainly enriched in extracellular matrix and cell adhesion, and KEGG confirmed that DEGs were mainly associated with focal adhesion, the PI3K-Akt signaling pathway, extracellular matrix- (ECM)- receptor interaction, and gastric acid secretion. 15 hub DEGs (BGN, COL1A1, COL1A2, FBN1, FN1, SPARC, SPP1, TIMP1, UBE2C, CCNB1, CD44, CXCL8, COL3A1, COL5A2, and THBS1) were identified from the PPI network. Furthermore, the survival analysis indicate that GC patients with a high expression of the following 9 hub DEGs, namely, BGN, COL1A1, COL1A2, FBN1, FN1, SPARC, SPP1, TIMP1, and UBE2C, had significantly worse overall survival. The circRNA-miRNA-mRNA network was constructed based on 1 circRNA, 15 miRNAs, and 45 DEGs. In addition, the 45 DEGs included 5 hub DEGs. These results suggested that hub DEGs and circRNAs could be implicated in the pathogenesis and development of GC. Our findings provide novel evidence on the circRNA-miRNA-mRNA network and lay the foundation for future research of circRNAs in GC.

SUBMITTER: Tian Y

PROVIDER: S-EPMC7463386 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Bioinformatics Analysis of Key Genes and circRNA-miRNA-mRNA Regulatory Network in Gastric Cancer.

Tian Yiting Y Xing Yang Y Zhang Zheng Z Peng Rui R Zhang Luyu L Sun Yan Y

BioMed research international 20200822

Gastric cancer (GC) is one of the most common malignancies in the world, with morbidity and mortality ranking second among all cancers. Accumulating evidences indicate that circular RNAs (circRNAs) are closely correlated with tumorigenesis. However, the mechanisms of circRNAs still remain unclear. This study is aimed at determining hub genes and circRNAs and analyzing their potential biological functions in GC. Expression profiles of mRNAs and circRNAs were downloaded from the Gene Expression Om ...[more]

PMID: 32908877

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Project description:BACKGROUND As all we know, gastric cancer (GC) is a highly aggressive disease. Recently, circular RNA (circRNA) was found to play a vital role in regulation of GC. Some circRNAs could regulate messenger RNA (mRNA) expression by functioning as a microRNA (miRNA) sponge. Nevertheless, the circRNA-miRNA-mRNA regulatory network involved GC rarely has been explored and researched. MATERIAL AND METHODS All the differentially expressed circRNAs, miRNAs, and mRNA were derived from Gene Expression Omnibus (GEO) microarray data (GSE78092, GSE89143, GSE93415, and GSE54129). GC level 3 miRNA-sequencing data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Furthermore, a circRNA-miRNA-mRNA regulatory network was constructed by Cytoscape (version 3.6.1). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed the functions and signaling pathways associated with these target genes. Hub genes of protein-protein interaction (PPI) network were identified by STRING database and cytoHubba. RESULTS The regulatory network consists of 3 circRNAs, 22 miRNAs, and 128 mRNAs. Only 3 miRNAs of the network were consistent with the expression of TCGA and were associated with some clinical features. The results of the functional analysis of 128 mRNAs showed that GO analysis and KEGG pathways of inclusion criteria were 49 and 24, respectively. PPI network and Cytoscape showed that the top 10 hub genes were MYC, CTGF, TGFBR2, TGFBR1, SERPINE1, KRAS, ZEB1, THBS1, CDK6, and TNS1; 4 of which were verified by GEPIA based on TCGA. Highly expressed SERPINE1 had a poor OS (over survival) and DFS (disease-free survival), and TGFBR1 expression increased along with the increase of clinical stages. CONCLUSIONS This study looked at a circRNA-miRNA-mRNA regulatory network associated with GC and explored the potential functions of mRNA in the network, then identified a new molecular marker for prediction, prognosis, and therapeutic targets for clinical patients.

Project description:The pathogenesis of gastric cancer (GC) is still not fully understood. We aimed to find the potential regulatory network for ceRNA (circRNA-miRNA-immune-related mRNA) to uncover the pathological molecular mechanisms of GC. The expression profiles of circRNA, miRNA, and mRNA in gastric tissue from GC patients were downloaded from the Gene Expression Omnibus (GEO) datasets. Differentially expressed circRNAs, miRNAs, and immune-related mRNAs were filtered, followed by the construction of the ceRNA (circRNA-miRNA-immune-related mRNA) network. Functional annotation and protein-protein interaction (PPI) analysis of immune-related mRNAs in the network were performed. Expression validation of circRNAs and immune-related mRNAs was performed in the new GEO and TCGA datasets and in-vitro experiment. A total of 144 differentially expressed circRNAs, 216 differentially expressed miRNAs, and 2,392 differentially expressed mRNAs were identified in GC. Some regulatory pairs of circRNA-miRNA-immune-related mRNA were obtained, including hsa_circ_0050102-hsa-miR-4537-NRAS-Tgd cells, hsa_circ_0001013-hsa-miR-485-3p-MAP2K1-Tgd cells, hsa_circ_0003763-hsa-miR-145-5p-FGF10-StromaScore, hsa_circ_0001789-hsa-miR-1269b-MET-adipocytes, hsa_circ_0040573-hsa-miR-3686-RAC1-Tgd cells, and hsa_circ_0006089-hsa-miR-5584-3p-LYN-neurons. Interestingly, FGF10, MET, NRAS, RAC1, MAP2K1, and LYN had potential diagnostic value for GC patients. In the KEGG analysis, some signaling pathways were identified, such as Rap1 and Ras signaling pathways (involved NRAS and FGF10), Fc gamma R-mediated phagocytosis and cAMP signaling pathway (involved RAC1), proteoglycans in cancer (involved MET), T-cell receptor signaling pathway (involved MAP2K1), and chemokine signaling pathway (involved LYN). The expression validation of hsa_circ_0003763, hsa_circ_0004928, hsa_circ_0040573, FGF10, MET, NRAS, RAC1, MAP2K1, and LYN was consistent with the integrated analysis. In conclusion, the identified ceRNA (circRNA-miRNA-immune-related mRNA) regulatory network may be associated with the development of GC.

Project description:Background: Osteoarthritis (OA) is a degenerative joint disease that seriously affects the quality of people. Unfortunately, the pathogenesis of OA has not been fully known. Therefore, this study aimed to construct a ceRNA regulatory network related to OA to explore the pathogenesis of OA. Methods: Differentially expressed circRNAs (DEcircRNAs), microRNAs (DEmiRNAs), and mRNAs (DEmRNAs) were obtained from the Gene Expression Omnibus microarray data (GSE175959, GSE105027, and GSE169077). The miRNA response elements and target mRNAs were identified using bioinformatics approaches. Additionally, a circRNA-miRNA-mRNA network was established using Cytoscape version 3.8.0. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of mRNAs in the network were conducted to explore the possible mechanisms underlying OA development. Protein-protein interaction (PPI) analysis was performed to determine the hub genes. Based on the hub genes, a sub network was constructed using Cytoscape 3.8.0 version. Finally, connectivity map (CMap) and drug-gene interaction database (DGIdb) analyses were performed to identify the potential therapeutic targets for OA. Results: Altogether, five DEcircRNAs, 89 DEmiRNAs, and 345 DEmRNAs were identified. Moreover, a circRNA-miRNA-mRNA network was established using three circRNAs, seven miRNAs, and 37 mRNAs. GO and KEGG analyses demonstrated that the mRNAs in the network could be related to the occurrence and development of OA. PPI analysis was performed and six key genes, namely serpin family H member 1 [SERPINH1], collagen type VIII alpha 2 chain [COL8A2], collagen type XV alpha 1 chain [COL15A1], collagen type VI alpha 3 chain [COL6A3], collagen type V alpha 1 chain [COL5A1], and collagen type XI alpha 1 chain [COL11A1], were identified. Furthermore, a circRNA-miRNA-hub gene subnetwork was established in accordance with two circRNAs (hsa_circ_0075320 and hsa_circ_0051428), two miRNAs (hsa-miR-6124 and hsa-miR-1207-5p), and six hub genes (COL11A1, SERPINH1, COL6A3, COL5A1, COL8A2, and COL15A1). Finally, three chemicals (noscapine, diazepam, and TG100-115) based on CMap analysis and two drugs (collagenase Clostridium histolyticum and ocriplasmin) based on DGIdb were discovered as potential treatment options for OA. Conclusion: This study presents novel perspectives on the pathogenesis and treatment of OA based on circRNA-related competitive endogenous RNA regulatory networks.

Project description:BackgroundCircular RNAs (circRNAs) were known to be related to the pathogenesis of many diseases through competing endogenous RNA (ceRNA) regulatory mechanisms. However, the function of circRNA in coronary artery disease (CAD) remains unclear. In this study, we aim to construct a circRNA-related competing endogenous RNA (ceRNA) network in CAD.MethodsThe gene expression profiles of CAD were obtained from Gene Expression Omnibus datasets. Bioinformatics analysis was performed to construct a ceRNA regulatory network, from which the hub genes involved were identified through protein-protein interaction (PPI) networks leading to the identification of the circRNA-miRNA-hub gene subnetwork. In addition, function enrichment analysis was performed to detect the potential biological mechanism in which circRNA might be involved.ResultsA total of 115 DEcircRNAs (differentially expressed circRNAs), 17 DEmiRNAs (differentially expressed microRNAs), and 790 DEmRNAs (differentially expressed mRNAs) were identified between CAD and control groups from microarray datasets. Functional enrichment analysis showed that DEmRNAs were significantly involved in inflammation-related pathways and ubiquitin-protein ligase binding. After identifying 20 DEcircRNA-DEmiRNA pairs and 561 DEmiRNA-DEmRNA pairs, we obtained a circRNA-miRNA-mRNA regulatory network. PPI network analysis showed that eight hub genes were closely related to CAD, leading to the identification of a circRNA-miRNA-hub gene subnetwork consisting of nine circRNAs (hsa_circ_0020275, hsa_circ_0020387, hsa_circ_0020417, hsa_circ_0045512, hsa_circ_0047336, hsa_circ_0069094, hsa_circ_0071326, hsa_circ_0071330, and hsa_circ_0085340), four miRNAs (hsa-miR-136-5p, hsa-miR-376c-3p, hsa-miR-411-5p, and hsa-miR-654-5p), and eight mRNAs (MKRN1, UBE2H, UBE2W, UBE2D1, UBE2F, BE2J1, ZNRF1, and SIAH2). In addition, we discovered these hub genes were enriched in the ubiquitin-mediated proteolysis pathway, suggesting circRNAs may be involved in the pathogenesis of CAD through this pathway.ConclusionsThis study may deepen our understanding of the potential role of circRNA-miRNA-mRNA regulation network in CAD and suggest novel diagnostic biomarkers and therapeutic targets for CAD.

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Bioinformatics Analysis of Key Genes and circRNA-miRNA-mRNA Regulatory Network in Gastric Cancer.

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Bioinformatics Analysis of Key Genes and circRNA-miRNA-mRNA Regulatory Network in Gastric Cancer.

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