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Identification of ceRNA network based on a RNA-seq shows prognostic lncRNA biomarkers in human lung adenocarcinoma.

ABSTRACT: Previous studies have emphasized the significant functions of long non-coding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) in tumor biology. However, the functions of certain cancer lncRNAs in the lncRNA-related ceRNA network in lung adenocarcinoma (LUAD) are unknown. A systematic and integrative survey of RNA-seq data from The Cancer Genome Atlas (TCGA) was performed to identify candidate lncRNAs for the prognosis of LUAD. In total, 20,502 genes that contain 181 lncRNAs were evaluated in a cohort of 570 LUAD cases. Initially, 6,280 differentially expressed genes (fold-change >2, P<0.05) were obtained using R package, which includes 75 lncRNAs. Next, by univariate regression and multivariate Cox proportional hazards analysis, 32 genes were associated with survival in LUAD. Using these 29 mRNAs and 3 lncRNAs, a prognosis index (PI) was calculated to accurately estimate the survival in LUAD: PI=?exprisk gene × HRrisk gene. Furthermore, the 32-gene signature was an independent prognostic indicator for LUAD (HR >1; P<0.05, by multivariate analysis). Weighted gene co-expression network analysis (WGCNA) of three risk lncRNAs-FAM138B, NHEG1 and TLX1NB-was performed, based on the P-values of the associated genes, and the top 27 miRNAs that bound to these lncRNAs were predicted by Miranda as target miRNAs. Next, these target miRNAs were transferred to the TarBase, miRTarBase, miRecards and starBase v2.0 databases to obtain their target genes. According to the previous miRNA-mRNA and miRNA-lncRNA data, three lncRNA-miRNA-mRNA ceRNA networks were established, based on the 29 prognostic mRNAs, forming a regulatory network in LUAD. The present study provided insight into the lncRNA-related ceRNA network in LUAD and has identified potential diagnostic and prognostic biomarkers.

SUBMITTER: Li X

PROVIDER: S-EPMC6176255 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Identification of ceRNA network based on a RNA-seq shows prognostic lncRNA biomarkers in human lung adenocarcinoma.

Li Xing X Li Bing B Ran Pixin P Wang Lanying L

Oncology letters 20180821 5

Previous studies have emphasized the significant functions of long non-coding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) in tumor biology. However, the functions of certain cancer lncRNAs in the lncRNA-related ceRNA network in lung adenocarcinoma (LUAD) are unknown. A systematic and integrative survey of RNA-seq data from The Cancer Genome Atlas (TCGA) was performed to identify candidate lncRNAs for the prognosis of LUAD. In total, 20,502 genes that contain 181 lncRNAs were evaluated i ...[more]

PMID: 30344725

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Project description: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.

Project description:BackgroundA growing body of evidence indicates that long non-coding RNAs (lncRNAs) can act as competitive endogenous RNAs (ceRNAs) to bind to microRNAs (miRNAs), thereby affecting and regulating the expression of target genes. The lncRNA-miRNA-mRNA ceRNA network has been theorized to play an indispensable role in many types of tumors. However, the role of the lncRNA-related ceRNA regulatory network in lung adenocarcinoma (LUAD) remains unclear.MethodsWe downloaded the RNAseq and miRNAseq data of LUAD from The Cancer Genome Atlas (TCGA) data portal and identified differentially expressed lncRNAs (DElncRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) between LUAD and corresponding paracancerous tissues by using the edgeR package of R software. We constructed the lncRNA-miRNA-mRNA ceRNA network by using Cytoscape (version 3.7.2) on the basis of the interaction generated from the miRcode, miRTarBase, miRDB, and TargetScan databases. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed with DAVID 6.8 bioinformatics resources and plotted by using the ggplot2 package in R. The effect of genes on LUAD prognosis was assessed by applying the survival package in R in accordance with the Kaplan-Meier curve.ResultsIn total, 1645 DElncRNAs, 117 DEmiRNAs, and 2729 DEmRNAs were identified in LUAD. The LUAD-specific ceRNA network was composed of 157 nodes and 378 edges (329 DElncRNA-DEmiRNA interactions and 49 DEmiRNA-DEmRNA interactions). GO and KEGG pathway annotations suggested that the LUAD-specific ceRNA network was related to tumor-related molecular functions and pathways. Seven lncRNAs (DISC1-IT1, SYNPR-AS1, H19, LINC00460, LINC00518, DSCR10, and STEAP2-AS1), one miRNA (hsa-mir-31), and 16 mRNAs (ATAD2, OSCAR, KIF23, E2F7, PFKP, MCM4, CEP55, CBX2, CCNE1, CLSPN, CCNB1, CDC25A, EZH2, CHEK1, SLC7A11, and PBK) were revealed to be significantly correlated with overall survival.ConclusionIn this study, we described the potential regulatory mechanism of the progression of LUAD. We proposed a new lncRNA-miRNA-mRNA ceRNA network that could help further explore the molecular mechanisms of LUAD.

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:Precision therapy for lung cancer will require comprehensive genomic testing to identify actionable targets as well as ascertain disease prognosis. RNA-seq is a robust platform that meets these requirements, but microarray-derived prognostic signatures are not optimal for RNA-seq data. Thus, we undertook the first prognostic analysis of lung adenocarcinoma RNA-seq data and generated a prognostic signature.Lung adenocarcinoma RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) were divided chronologically into training (n?=?255) and validation (n?=?157) cohorts. In the training cohort, prognostic association was assessed by univariate Cox analysis. A prognostic signature was built with stepwise multivariable Cox analysis. Outcomes by risk group, stage, and mutation status were analyzed with Kaplan-Meier and multivariable Cox analyses. All the statistical tests were two-sided.In the training cohort, 96 genes had prognostic association with P values of less than or equal to 1.00x10-4, including five long noncoding RNAs (lncRNAs). Stepwise regression generated a four-gene signature, including one lncRNA. Signature high-risk cases had worse overall survival (OS) in the TCGA validation cohort (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 2.00 to 14.62) and a University of Michigan institutional cohort (n?=?67; HR?=?2.05, 95% CI?=?1.18 to 4.55), and worse metastasis-free survival in the TCGA validation cohort (HR?=?3.05, 95% CI?=?2.31 to 13.37). The four-gene prognostic signature also statistically significantly stratified overall survival in important clinical subsets, including stage I (HR?=?2.78, 95% CI?=?1.91 to 11.13), EGFR wild-type (HR?=?3.01, 95% CI?=?1.73 to 14.98), and EGFR mutant (HR?=?8.99, 95% CI?=?62.23 to 141.44). The four-gene prognostic signature also stood out on top when compared with other prognostic signatures.Here, we present the first RNA-seq prognostic signature for lung adenocarcinoma that can provide a powerful prognostic tool for precision oncology as part of an integrated RNA-seq clinical sequencing program.

Dataset Information

Identification of ceRNA network based on a RNA-seq shows prognostic lncRNA biomarkers in human lung adenocarcinoma.

Publications

Identification of ceRNA network based on a RNA-seq shows prognostic lncRNA biomarkers in human lung adenocarcinoma.

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