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Comprehensive analysis of TPX2-related ceRNA network as prognostic biomarkers in lung adenocarcinoma.

ABSTRACT: Background and aim: Competing endogenous RNA (ceRNA) is believed to play vital roles in tumorigenesis. The goal of this study was to screen prognostic biomarkers in lung adenocarcinoma (LUAD). Methods: Common differentially expressed genes (DEGs) were collected from Gene Expression Omnibus (GEO) databases and The Cancer Genome Atlas databases (TCGA) using GEO2R and "limma" package in R, respectively. Overlapping DEGs were conducted using enrichment of functions and protein-protein interaction (PPI) network to discover significant candidate genes. By using a comprehensive analysis, we constructed an mRNA mediated ceRNA network. Survival rates were used Kaplan-Meier analysis. Statistical analysis was used to further identify the prognosis of studied genes. Results: Integrated analysis of GSE32863 and TCGA databases, a total of 886 overlapping DEGs, including 279 up-regulated and 607 down-regulated genes were identified. Considering the highest term of candidate genes in PPI, we identified TPX2, which was enriched in cell division signaling pathway. Besides, 35 differentially expressed miRNAs (DEmiRNAs) were predicted to target TPX2 and only 7 DEmiRNAs were identified to be prognostic biomarkers in LUAD. Then, 30 differentially expressed lncRNAs (DElncRNAs) were predicted to bind these 7 DEmiRNAs. Finally, we found that 7 DElncRNAs were correlated with the overall survival (all p <0.05). Furthermore, we identified elevated TPX2 was strongly correlated with the worse survival rate among 458 samples. Univariate and multivariate cox analysis showed TPX2 may act as an independent factor for prognosis in LUAD (p <0.05). Then pathway enrichment results suggested that TPX2 may facilitate tumorigenesis by participating in several cancer-related signaling pathways in LUAD, especially in Notch signal pathway. Conclusions: TPX2-related lncRNAs and miRNAs are related to the survival of LUAD. 7 lncRNAs, 7 miRNAs and TPX2 may serve as prognostic biomarkers in LUAD.

SUBMITTER: Huo C

PROVIDER: S-EPMC7532481 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Comprehensive analysis of TPX2-related ceRNA network as prognostic biomarkers in lung adenocarcinoma.

Huo Chen C Zhang Meng-Yu MY Li Rui R Zhou Xi-Jia XJ Liu Ting-Ting TT Li Jian-Ping JP Liu Xiao X Qu Yi-Qing YQ

International journal of medical sciences 20200901 16

<b>Background and aim:</b> Competing endogenous RNA (ceRNA) is believed to play vital roles in tumorigenesis. The goal of this study was to screen prognostic biomarkers in lung adenocarcinoma (LUAD). <b>Methods:</b> Common differentially expressed genes (DEGs) were collected from Gene Expression Omnibus (GEO) databases and The Cancer Genome Atlas databases (TCGA) using GEO2R and "limma" package in R, respectively. Overlapping DEGs were conducted using enrichment of functions and protein-protein ...[more]

PMID: 33029085

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Project description:BackgroundMore and more studies have proven that circular RNAs (circRNAs) play vital roles in cancer development via sponging miRNAs. However, the expression pattern of competing endogenous RNA (ceRNA) in lung adenocarcinoma (LUAD) remains largely unclear. The current study explored functional roles and the regulatory mechanisms of circRNA as ceRNAs in LUAD and their potential impact on LUAD patient prognosis.MethodsIn this study, we systematically screened differential expression circRNAs (DEcircRNAs), miRNAs (DEmiRNAs) and mRNAs (DEGs) associated with LUAD. Then, DEcircRNAs, DEmiRNAs and DEGs were selected to construct a circRNA-miRNA-mRNA prognosis-related regulatory network based on interaction information from the ENCORI database. Subsequently, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the genes in the network to predict the potential underlying mechanisms and functions of circRNAs in LUAD. In addition, Kaplan-Meier survival analysis was performed to evaluate clinical outcomes of LUAD patients, and drug sensitivity analysis was used to screen potential biomarkers for drug treatment of patients with LUAD.ResultsAs a result, 10 circRNAs were aberrantly expressed in LUAD tissues. The ceRNA network was built, which included 3 DEcircRNAs, 6 DEmiRNAs and 157 DEGs. The DEGs in the ceRNA network of hsa_circ_0049271 enriched in biological processes of cell proliferation and the Jak-STAT signaling pathway. We also detected 7 mRNAs in the ceRNA network of hsa_circ_0049271 that were significantly associated with the overall survival of LUAD patients (P < 0.05). Importantly, four genes (PDGFB, CCND2, CTF1, IL7R) identified were strongly associated with STAT3 activation and drugs sensitivity in GDSC.ConclusionsIn summary, a ceRNA network of hsa_circ_0049271 was successfully constructed, which including one circRNA, two miRNAs, and seven mRNAs. Seven mRNAs (PDGFB, TNFRSF19, CCND2, CTF1, IL11RA, IL7R and MAOA) were remarkably associated with the prognosis of LUAD patients. Among seven mRNA species, four genes (PDGFB, CCND2, CTF1, and IL7R) could be considered as drug targets in LUAD. Our research will provide new insights into the prognosis-related ceRNA network in LUAD.

Project description:IntroductionThe regulatory mechanisms of super enhancers (SEs) and ceRNA networks in LUAD progression are not well understood. We aimed to discover the prognostic-related ceRNA network regulated by SEs in metastatic LUAD.MethodsRNA-seq data were extracted from The Cancer Genome Atlas (TCGA) database. Differentially expressed (DE) RNAs were identified by edgeR. CeRNA network was predicted and visualized using starBase and Cytoscape. H3K27ac ChIP-seq data were derived from the Gene Expression Omnibus (GEO) database, and used for SE identification. Kaplan-Meier curve and multivariate Cox model were applied for prognostic analysis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network were performed for functional analysis. SEs of AC074117.1 were verified by ChIP-qPCR in A549 and H1299 cells. MTT assay was performed to analyze cell proliferation. Luciferase activity assay was carried out to validate the target targeting relationships of ceRNA network.ResultsA total of 2355 DEmRNA, 483 DElncRNA and 155 DEmiRNA were identified between metastatic LUAD and adjacent normal tissues. CeRNA network consisting of 7 DElncRNAs, 18 DEmiRNAs and 15 DEmRNAs was constructed. Among the seven DElncRNAs in ceRNA network, only AC074117.1 was regulated by SEs. SE-regulated prognostic ceRNA sub-network consisting of FKBP3, E2F2, AC074117.1 and hsa-let-7c-5p was screened and verified. The overlapping co-expressed mRNAs of FKBP3, E2F2, AC074117.1 and hsa-let-7c-5p were mainly related to cell division and Fanconi anemia pathway. Genes in the ceRNA sub-network were correlated with DNA mismatch repair markers. Functional experiments proved that AC074117.1 was highly expressed in LUAD cells. AC074117.1 silencing notably inhibited proliferation of A549 and H1299 cells. Luciferase activity assay confirmed the direct relationship in AC074117.1-hsa-let-7c-5p-FKBP3/E2F2 network.ConclusionA novel prognostic ceRNA sub-network regulated by SEs was identified in metastatic LUAD. This study provided potential therapeutic targets and prognostic markers for further study of metastatic LUAD.

Project description:BACKGROUND We aimed to screen and identify central genetic and molecular targets involved in advancement of lung adenocarcinoma (LUAD) and to perform an integrated analysis and clinical validation. MATERIAL AND METHODS The GEO2R technique was utilized to assess differentially expressed genes (DEGs) among the gene sets GSE75037, GSE85716, and GSE118370. Subsequently, gene Ontology (GO) analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) analytical methods were executed to determine related biofunctions and signaling pathways, which were annotated with tools from the Database for Annotation, Visualization and Integrated Discovery (DAVID) resource. Then, a protein-protein interaction (PPI) network complex consisting of all detected DEGs was built with the STRING web interface. Cytohubba and MCODE plug-ins for Cytoscape software and Gene Expression Profiling Interactive Analysis (GEPIA) were employed to identify the hub genes. Finally, the mRNA expression of the identified hub genes was quantitatively validated by The Cancer Genome Atlas (TCGA) database analysis and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS We screened 146 upregulated DEGs and 431 downregulated DEGs with the criteria of |logFC| >1 and P<0.05, and the GO analysis indicated that DEGs were implicated in mitotic nuclear division (biological process, BP), the nucleus (cellular component, CC), and protein binding (molecular function, MF) and were associated with multiple KEGG pathways, such as the p53 signaling pathway in cancer. Then, the top 8 genes that predicted significantly different outcomes in LUAD patients were filtered from the DEGs and selected as hub genes. The TCGA database analysis and RT-qPCR results demonstrated that these genes were differentially expressed with the same trends in LUAD tissues compared with normal tissues. CONCLUSIONS Overall, we propose that 8 genes (PECAM1, CDK1, MKI67, SPP1, TOP2A, CHEK1, CCNB1, and RRM2) might be novel hub genes strongly associated with the progression and prognosis of LUAD.

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Comprehensive analysis of TPX2-related ceRNA network as prognostic biomarkers in lung adenocarcinoma.

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Comprehensive analysis of TPX2-related ceRNA network as prognostic biomarkers in lung adenocarcinoma.

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