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Integrated analysis of lncRNA-associated ceRNA network reveals potential biomarkers for the prognosis of hepatitis B virus-related hepatocellular carcinoma.

ABSTRACT: Background:There is evidence that abnormal expression of lncRNAs is associated with hepatitis B virus (HBV) infection-induced hepatocellular carcinoma (HCC). However, the mechanisms remain not fully elucidated. The study aimed to identify novel lncRNAs and explore their underlying mechanisms based on the ceRNA hypothesis. Methods:The RNA and miRNA expression profiling in 20 tumor and matched adjacent tissues from HBV-HCC patients were retrieved from the Gene Expression Omnibus database under accession numbers GSE77509 and GSE76903, respectively. Differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs) were identified using the EdgeR package. Protein-protein interaction (PPI) network was constructed for DEGs followed by module analysis. The ceRNA network was constructed based on interaction relationships between miRNAs and mRNAs/lncRNAs. The functions of DEGs were predicted using DAVID and BinGO databases. The prognosis values (overall survival [OS] and recurrence-free survival [RFS]) of ceRNA network genes were determined using The Cancer Genome Atlas (TCGA) data with Cox regression analysis and Kaplan-Meier method. Results:The present study screened 643 DELs, 83 DEMs, and 1,187 DEGs. PPI network analysis demonstrated that CDK1 and CCNE1 were hub genes and extracted in functionally related modules. E2F2, CDK1, and CCNE1 were significantly enriched into cell cycle pathway. FAM182B-miR-125b-5p-E2F2 and LINC00346-miR-10a-5p-CDK1/CCNE1 ceRNA axes were obtained by constructing the ceRNA network. Patients with high expressions of DELs and DEGs in the above ceRNA axes had poor OS, while patients with the high expression of DEMs possessed excellent OS. CDK1 was also an RFS-related biomarker, with its high expression predicting poor RFS. The upregulation of LINC00346 and CDK1 but the downregulation of miR-10a-5p in HCC was validated in other microarray datasets and TCGA database. Conclusion:The LINC00346-miR-10a-5p-CDK1 axis may be an important mechanism for HBV-related HCC, and genes in this ceRNA axis may be potential prognostic biomarkers and therapeutic targets.

SUBMITTER: Li H

PROVIDER: S-EPMC6340501 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Integrated analysis of lncRNA-associated ceRNA network reveals potential biomarkers for the prognosis of hepatitis B virus-related hepatocellular carcinoma.

Li Hongyan H Zhao Xiaonan X Li Chenghua C Sheng Chuanlun C Bai Zhenzi Z

Cancer management and research 20190117

<h4>Background</h4>There is evidence that abnormal expression of lncRNAs is associated with hepatitis B virus (HBV) infection-induced hepatocellular carcinoma (HCC). However, the mechanisms remain not fully elucidated. The study aimed to identify novel lncRNAs and explore their underlying mechanisms based on the ceRNA hypothesis.<h4>Methods</h4>The RNA and miRNA expression profiling in 20 tumor and matched adjacent tissues from HBV-HCC patients were retrieved from the Gene Expression Omnibus dat ...[more]

PMID: 30697079

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Project description:Background:Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis and a high incidence. The molecular changes and novel biomarkers of HCC need to be identified to improve the diagnosis and prognosis of this disease. We investigated the current research concentrations of HCC and identified the transcriptomics-related biomarkers of HCC from The Cancer Genome Atlas (TGCA) database. Methods:We investigated the current research concentrations of HCC using literature metrology analysis for studies conducted from 2008 to 2018. We identified long noncoding RNAs (lncRNAs) that correlated with the clinical features and survival prognoses of HCC from The Cancer Genome Atlas (TGCA) database. Differentially expressed genes (lncRNAs, miRNAs, and mRNAs) were also identified by TCGA datasets in HCC tumor tissues. A lncRNA competitive endogenous RNA (ceRNA) network was constructed from lncRNAs based on intersected lncRNAs. Survival times and the association between the expression levels of the key lncRNAs of the ceRNA network and the clinicopathological characteristics of HCC patients were analyzed using TCGA. Real-time polymerase chain reaction (qRT-PCR) was used to validate the reliability of the results in tissue samples from 20 newly-diagnosed HCC patients. Results:Analysis of the literature pertaining to HCC research revealed that current research is focused on lncRNA functions in tumorigenesis and tumor development. A total of 128 HCC dysregulated lncRNAs were identified; 66 were included in the co-expressed ceRNA network. We analyzed survival times and the associations between the expression of 66 key lncRNAs and the clinicopathological features of the HCC patients identified from TCGA. Twenty-six lncRNAs were associated with clinical features of HCC (P < 0.05) and six key lncRNAs were associated with survival time (log-rank test P < 0.05). Six key lncRNAs were selected for the validation of their expression levels in 20 patients with newly diagnosed HCC using qRT-PCR. Consistent fold changes in the trends of up and down regulation between qRT-PCR validation and TCGA proved the reliability of our bioinformatics analysis. Conclusions:We used integrative bioinformatics analysis of the TCGA datasets to improve our understanding of the regulatory mechanisms involved with the functional features of lncRNAs in HCC. The results revealed that lncRNAs are potential diagnostic and prognostic biomarkers of HCC.

Project description:ObjectiveThis study aims to construct a systematic mRNA-miRNA-lncRNA network to identify novel lncRNAs and miRNAs biomarkers for laryngeal squamous cell carcinoma (LSCC).MethodsThe mRNA, miRNA and lncRNA expression profiles of LSCC were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed mRNAs, miRNAs and lncRNAs (DEmRNAs, DEmiRNAs and DElncRNAs) were screened between LSCC tissues and controls. Functional analysis of DEmRNAs, DEmRNAs targeted by DEmiRNAs and DEmRNAs targeted by DElncRNAs were respectively performed. The miRWalk, starbase and DIANA-LncBase were respectively used to predict DEmiRNAs-DEmRNAs, DElncRNAs-DEmRNAs and DElncRNAs-DEmiRNAs pairs. ceRNA network was built by DEmiRNAs-DEmRNAs and DElncRNAs-DEmiRNAs pairs. LncRNA subcellular localization was predicted using lncLocator. Using published The Cancer Genome Atlas (TCGA) and external datasets (GSE127165 and GSE133632), we also validated the expression of key DElncRNAs and DEmiRNAs in ceRNA network. The diagnostic and prognostic value of candidate genes was evaluated by ROC curve analysis and survival analysis, respectively.ResultsThere were 5 mRNA datasets, 3 miRNA datasets and 2 lncRNA datasets in this study. Totally, 2957 DEmRNAs, 61 DElncRNAs and 23 DEmiRNAs were identified. Functional analysis of DEmRNAs shows that they were significantly enriched in cancer-related pathways, such as DNA replication and extracellular matrix organization. There were 11 DEmiRNAs, 17 DElncRNAs and 967 DEmRNAs in the ceRNA network. Notably, up-regulated lncRNA DGCR5-down-regulated has-miR-338-3p/has-miR-139-5p pairs in this network were experimentally validated. Moreover, down-regulated AL121839.2, down-regulated LINC02147, up-regulated AC079328.2, up-regulated AC004943.2 and up-regulated HMGA2-AS1 were located in the cytoplasm. AL121839.2 and LINC02147 interacted with has-miR-1246. AC004943.2, AC079328.2 and HMGA2-AS1 targeted has-miR-3185, has-miR-3137 and has-miR-582-5p, respectively. Based on the TCGA and external datasets (GSE127165 and GSE133632), DGCR5 and AC004943.2 were significantly up-regulated while AL121839.2 and LINC02147, has-miR-338-3p, has-miR-139-5p and has-miR-582-5p were significantly down-regulated, which were consistent with our integration analysis. DGCR5, AL121839.2, LINC02147, AC004943.2, has-miR-338-3p, has-miR-139-5p and has-miR-582-5p could predict the occurrence of LSCC. Survival analysis suggested that only, AL121839.2 has potential prognostic value for LSCC.ConclusionThis study provided novel insights into the ceRNA network and uncovered novel lncRNAs and miRNAs with diagnostic value in LSCC.

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.

Dataset Information

Integrated analysis of lncRNA-associated ceRNA network reveals potential biomarkers for the prognosis of hepatitis B virus-related hepatocellular carcinoma.

Publications

Integrated analysis of lncRNA-associated ceRNA network reveals potential biomarkers for the prognosis of hepatitis B virus-related hepatocellular carcinoma.

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