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Characterization of Dysregulated lncRNA-Associated ceRNA Network Reveals Novel lncRNAs With ceRNA Activity as Epigenetic Diagnostic Biomarkers for Osteoporosis Risk.

ABSTRACT: The altered expression of long non-coding RNAs (lncRNAs) has been implicated in the development and human diseases. However, functional roles and regulatory mechanisms of lncRNA as competing endogenous RNAs (ceRNAs) in osteoporosis and their potential clinical implication for osteoporosis risk are largely unexplored. In this study, we performed integrated analysis for paired expression profiles and regulatory relationships of dysregulated lncRNAs, mRNAs, and miRNAs based on "ceRNA hypothesis," and constructed an osteoporosis-related dysregulated miRNA-mediated lncRNA-mRNA ceRNA network (DysCeNet) composed of 105 nodes (including eight miRNAs, 24 mRNAs, and 73 lncRNAs) and 515 edges. Functional analysis suggested that the DysCeNet was involved in known osteoporosis or bone metabolism-related biological processes and pathways. Then, we performed random forest-based feature selection for 73 lncRNAs with ceRNA activity and identified 25 of 73 lncRNAs as potential diagnostic biomarkers. A random forest-based classifier composed of 25 lncRNA biomarkers (RF-25lncRNA) was developed for predicting osteoporosis risk. Performance evaluation with the leave-one-out cross-validation (LOOCV) procedure showed that the RF-25lncRNA achieved a good performance in distinguishing high- and low-bone mineral density (BMD) subjects in different osteoporosis datasets. Our study for the first time revealed a global view of lncRNA-associated ceRNA regulation in osteoporosis and provided novel lncRNAs with ceRNA activity as candidate epigenetic diagnostic biomarkers for early detection of osteoporosis risk.

SUBMITTER: Zhang M

PROVIDER: S-EPMC7136400 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Characterization of Dysregulated lncRNA-Associated ceRNA Network Reveals Novel lncRNAs With ceRNA Activity as Epigenetic Diagnostic Biomarkers for Osteoporosis Risk.

Zhang Meijie M Cheng Luyang L Zhang Yina Y

Frontiers in cell and developmental biology 20200331

The altered expression of long non-coding RNAs (lncRNAs) has been implicated in the development and human diseases. However, functional roles and regulatory mechanisms of lncRNA as competing endogenous RNAs (ceRNAs) in osteoporosis and their potential clinical implication for osteoporosis risk are largely unexplored. In this study, we performed integrated analysis for paired expression profiles and regulatory relationships of dysregulated lncRNAs, mRNAs, and miRNAs based on "ceRNA hypothesis," a ...[more]

PMID: 32296700

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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:BackgroundLong noncoding RNAs (lncRNAs) play important roles in competing endogenous RNA (ceRNA) networks involved in the development and progression of various cancers, including muscle-invasive bladder cancer (MIBC).PurposeThis study aims to construct the lncRNA-associated ceRNA network and identify lncRNA signatures correlated with the clinical features of MIBC tissue samples from The Cancer Genome Atlas (TGCA) database.MethodsThe differential expression profiles of MIBC associated lncRNAs, miRNAs and mRNAs were obtained from TCGA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to determine the principal functions of significantly dysregulated mRNAs. The dysregulated lncRNA-associated ceRNA network of MIBC was constructed based on the bioinformatics data, and the correlations between lncRNA expression and clinical features were analyzed using a weighted gene coexpression network analysis (WGCNA). Six cancer specific lncRNAs from the ceRNA network were randomly selected to detect their expression in 32 paired MIBC tissue samples and 5 bladder cancer cell lines using quantitative real-time polymerase chain reaction (qRT-PCR).ResultsThe ceRNA network was constructed with 30 lncRNAs, 13 miRNAs and 32 mRNAs. Seventeen lncRNAs in the ceRNA network correlated with certain clinical features, and only 1 lncRNA (MIR137HG) correlated with the overall survival (OS) of patients with MIBC (log-rank test P<0.05). GO and KEGG analyses revealed roles for the potential mRNA targets of MIR137HG in epithelial cell differentiation and the peroxisome proliferator-activated receptor (PPAR) and tumor necrosis factor (TNF) signaling pathways. The expression data from TCGA were highly consistent with the verification results of the MIBC tissue samples and bladder cancer cell lines.ConclusionThese findings improve our understanding of the regulatory mechanism of the lncRNA-miRNA-mRNA ceRNA network and reveal potential lncRNAs as prognostic biomarkers of MIBC.

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.

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Dataset Information

Characterization of Dysregulated lncRNA-Associated ceRNA Network Reveals Novel lncRNAs With ceRNA Activity as Epigenetic Diagnostic Biomarkers for Osteoporosis Risk.

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Characterization of Dysregulated lncRNA-Associated ceRNA Network Reveals Novel lncRNAs With ceRNA Activity as Epigenetic Diagnostic Biomarkers for Osteoporosis Risk.

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