Identification of pivotal lncRNAs in papillary thyroid cancer using lncRNA-mRNA-miRNA ceRNA network analysis.
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ABSTRACT:
SUBMITTER: Liang W
PROVIDER: S-EPMC6754980 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Project description:Long noncoding RNAs (lncRNAs) play important roles in tumorigenesis and progression of different cancers and they have been potential biomarkers for cancer diagnosis and prognosis. As the most common endocrine malignancy, precise diagnosis and prognosis of papillary thyroid cancer (PTC) is of great clinical significance. Here, we aim to identify new hub lncRNAs for marking PTC and constructed prognostics signatures based on lncRNA- miRNA-mRNA competing endogenous RNAs (ceRNA) network to predict overall survival (OS) and disease-free survival (DFS) respectively. Five reliable hub lncRNAs were identified by integrating differential genes of four Gene Expression Omnibus (GEO) gene chips using the RobustRankAggreg (RRA) method. Based on differential analyses and interaction prediction, a lncRNA-mRNA co-expression network and a lncRNA-miRNA-mRNA ceRNA network were established. Then a comprehensive function characterization of the five hub lncRNAs was performed, including validation dataset testing, receiver operating characteristic (ROC) curve analysis, and functional analysis on two networks. All results suggest that these five hub lncRNAs could be potential biomarkers for marking PTC. The ceRNA network was used to identify RNAs which were associated with PTC prognosis. Two prognostic signatures were developed using univariate and step-wise multivariate Cox regression analyses and both of them were independent prognostic indicators for PTC OS and DFS. Tumor microenvironment difference analysis between high and low-risk patients showed that dendritic cells activated and macrophages M0 may be a possible target for immunotherapy of PTC. In addition, disclosing the potential drugs that may reverse the expression of hub genes may improve the prognosis of patients with PTC. Here, connectivity map (CMap) analysis indicates that three bioactive chemicals (pioglitazone, benserazide, and SB-203580) are promising therapeutic agents for PTC. So, the paper presents a comprehensive study on diagnosis, prognosis, and potential drug screening for PTC based on the five hub lncRNAs identified by us.
| S-EPMC8548639 | biostudies-literature
Project description:The current focus in the treatment of papillary thyroid carcinoma (PTC) is tumor progression. The aim of this study was to build RNA-based classifiers and develop a comprehensive model to provide progression-free interval (PFI) risk prediction for PTC. The RNAseq data, miRNAseq data, and clinical information of PTC were downloaded from The Cancer Genome Atlas database. Based on the differently expressed RNAs, the least absolute shrinkage and selection operator (LASSO) Cox regression model was utilized to build the RNA-based classifiers for PFI of the patients with PTC. A 6-messenger RNA (mRNA)-based classifier, a 5-long non-coding RNA (lncRNA)-based classifier, and a 4-microRNA (miRNA)-based classifier were constructed to predict the PFI. Patients with high risk based on the constructed RNA-based classifiers had worse prognosis in Kaplan-Meier curve analysis with log-rank test. The areas under the curves of the first, third, and fifth years in the training and testing set were 0.83, 0.82, and 0.82 and 0.67, 0.72, and 0.73 for the 6-mRNA-based classifier, respectively; 0.75, 0.84, and 0.85 and 0.71, 0.67, and 0.71 for the 5-lncRNA-based classifier, respectively; and 0.70, 0.77, and 0.79 and 0.74, 0.67, and 0.66 for the 4-miRNA-based classifier, respectively. The prediction capability of the three RNA-based classifiers was superior to the TNM stage system. Furthermore, a nomogram based on the verified independent prognostic factors was established for the prognostic prediction. The C-index and calibration plots indicated good predictive accuracy of the nomogram. In summary, the 6-mRNA-based classifier and 5-lncRNA-based classifier constructed in this study were independent prognostic factors for PTC.
| S-EPMC7417634 | biostudies-literature
Project description:Accumulating evidence has indicated that long noncoding RNAs (lncRNAs) are the main constituents of competing endogenous RNA (ceRNA) networks. Nonetheless, in the lncRNA-related ceRNA network of papillary thyroid cancer (PTC), the function of cancer-specific lncRNAs, as well as their use for the potential prediction of PTC prognosis, remains unclear. In this study, 384 RNA sequencing (RNA-seq) profiles of PTC patients were attained from The Cancer Genome Atlas (TCGA), an open-source database that offers vast amounts of RNA-seq data, and 75 miRNAs, 495 lncRNAs, and 1099 mRNAs (P?<?.05 and |logFC| >2) were detected when compared with normal tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed using the Cytoscape plug-in BinGo. An aberrant lncRNA-mRNA-miRNA ceRNA network consisting of 31 differentially expressed (DE)-lncRNAs, 13 DE-miRNAs, and 134 DE-mRNAs was built in TCGA. On the basis of overall survival (OS) analysis, 6 lncRNAs (CCAT1, SYNPR, SFTA1P, HOTAIR, HCG22, and CLDN10) were identified as prognostic biomarkers for patients in TCGA (P?<?.05). Through qRT-PCR, we designated 6 cancer-specific lncRNAs as having great significance for survival by verifying their expression in the 60 PTC patients who were diagnosed. The qRT-PCR and TCGA results were completely consistent. Our research provides data for further understanding the lncRNA-miRNA-mRNA ceRNA network and elucidating the molecular mechanisms of PTC.
| S-EPMC7647549 | biostudies-literature
Project description:Accumulating evidence has indicated that noncoding RNAs are involved in intervertebral disc degeneration (IDD); however, the competing endogenous RNA (ceRNA)?mediated regulatory mechanisms in IDD remain rarely reported. The present study aimed to comprehensively investigate the alterations in expression levels of circular RNA (circRNA), long noncoding RNA (lncRNA), microRNA (miRNA/miR) and mRNA in the nucleus pulposus (NP) of patients with IDD. In addition, crucial lncRNA/circRNA?miRNA?mRNA ceRNA interaction axes were screened using the GSE67567 microarray dataset obtained from the Gene Expression Omnibus database. After data preprocessing, differentially expressed circRNAs (DECs), lncRNAs (DELs), miRNAs (DEMs) or genes (DEGs) between IDD and normal controls were identified using the Linear Models for Microarray data method. A protein?protein interaction (PPI) network was constructed for DEGs based on protein databases, followed by module analysis. The ceRNA network was constructed based on the interaction between miRNAs and mRNAs, and lncRNAs/circRNAs and miRNAs. The underlying functions of mRNAs were predicted using the Database for Annotation, Visualization and Integrated Discovery database. The present study identified 636 DECs, 115 DELs, 84 DEMs and 1,040 DEGs between patients with IDD and control individuals. PPI network analysis demonstrated that Fos proto?oncogene, AP?1 transcription factor subunit (FOS), mitogen?activated protein kinase 1 (MAPK1), hypoxia inducible factor 1 subunit ? (HIF1A) and transforming growth factor ?1 (TGFB1) were hub genes and enriched in modules. Metastasis?associated lung adenocarcinoma transcript 1 (MALAT1)/hsa_circRNA_102348?hsa??miR?185?5p?TGFB1/FOS, MALAT1?hsa?miR?155?5p?HIF1A, hsa_circRNA_102399?hsa?miR?302a?3p?HIF1A, MALAT1?hsa??miR?519d?3p?MAPK1 and hsa_circRNA_100086?hsa?miR?509?3p?MAPK1 ceRNA axes were obtained by constructing the ceRNA networks. In conclusion, these identified ceRNA interaction axes may be crucial targets for the treatment of IDD.
| S-EPMC6755180 | biostudies-literature
Project description:Increasing evidence has experimentally proved the competitive endogenous RNA (ceRNA) hypothesis that long non-coding RNA (lncRNA) can affect the expression of RNA targets by competitively combining microRNA (miRNA) via miRNA response elements. However, an extensive ceRNA network of thyroid carcinoma in a large cohort has not been evaluated. We analyzed the RNAseq and miRNAseq data of 348 cases of primary papillary thyroid cancer (PTC) patients with clinical information downloaded from The Cancer Genome Atlas (TCGA) project to search for potential biomarkers or therapeutic targets. A computational approach was applied to build an lncRNA-miRNA-mRNA regulatory network of PTC. In total, 780 lncRNAs were detected as collectively dysregulated lncRNAs in all 3 PTC variants compared with normal tissues (fold change >2 and false discovery rate <0.05). The interactions among 45 lncRNAs, 13 miRNAs and 86 mRNAs constituted a ceRNA network of PTC. Nine out of the 45 aberrantly expressed lncRNAs were related to the clinical features of PTC patients. However, the expression levels of 3 lncRNAs (LINC00284, RBMS3-AS1 and ZFX-AS1) were identified to be tightly correlated with the patients overall survival (log-rank, P<0.05). The present study identified a list of specific lncRNAs associated with PTC progression and prognosis. This complex ceRNA interaction network in PTC may provide guidance for better understanding the molecular mechanisms underlying PTC.
| S-EPMC5802034 | biostudies-literature
Project description:Papillary thyroid cancer (PTC) is one of the most common cancers worldwide, and its carcinogenesis is influenced by a complex network of gene interactions. In this study, the microarray expression profile was re-annotated into a lncRNA-mRNA biphasic profile. LncRNA-mRNA interactions were confirmed by established miRNA-RNA data and hypergeometric test. Then, a PTC-related lncRNA-miRNA-mRNA network (PTCRN) was constructed by integrating differentially expressed genes with the RNA-RNA networks. The new network consisted of 21 lncRNAs, 241 mRNAs and 803 edges. To prioritize PTC-related genes, we performed topological analysis and random walk with restart (PWR) algorithm analysis of PTCRN. Both analyses identified lncRNA RP11-159F24.1 as a hub node in the network, which could interact with 47 mRNAs by sponging miR-485. In functional enrichment analysis, these interacting mRNAs were associated with the pathways in cancer. In validation, RP11-159F24.1 (up-regulated; P = 0.0013) showed an opposite expression pattern with its target miR-485 (down-regulated; P = 0.0013) in PTC, indicating that the RP11-159F24.1/miR-485/mRNAs axis might play an important role in the development of PTC. In conclusion, this study has constructed a PTC-related lncRNA-miRNA-mRNA network and identified the hub lncRNA RP11-159F24.1 in the tumorigenesis, which provided novel insights to explore the underlying mechanism of PTC.
| S-EPMC6308055 | biostudies-literature
Project description:BackgroundMany studies on long chain non-coding RNAs (lncRNAs) are published in recent years. But the roles of lncRNAs in aortic dissection (AD) are still unclear and should be further examined. The present work focused on determining the molecular mechanisms underlying lncRNAs regulation in aortic dissection on the basis of the lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network.MethodsThis study collected the lncRNAs (GSE52093), mRNAs (GSE52093) and miRNAs (GSE92427) expression data within human tissue samples with aortic dissection group and normal group based on Gene Expression Omnibus (GEO) database.ResultsThis study identified three differentially expressed lncRNAs (DELs), 19 differentially expressed miRNAs (DEmiRs) and 1046 differentially expressed mRNAs (DEGs) identified regarding aortic dissection. Furthermore, we constructed a lncRNA-miRNA-mRNA network through three lncRNAs (including two with up-regulation and one with down-regulation), five miRNAs (five with up-regulation), as well as 211 mRNAs (including 103 with up-regulation and 108 with down-regulation). Simultaneously, we conducted functional enrichment and pathway analyses on genes within the as-constructed ceRNA network. According to our PPI/ceRNA network and functional enrichment analysis results, four critical genes were found (E2F2, IGF1R, BDNF and PPP2R1B). In addition, E2F2 level was possibly modulated via lncRNA FAM87A-hsa-miR-31-5p/hsa-miR-7-5p or lncRNA C9orf106-hsa-miR-7-5p. The expression of IGF1R may be regulated by lncRNA FAM87A-hsa-miR-16-5p/hsa-miR-7-5p or lncRNA C9orf106-hsa-miR-7-5p.ConclusionIn conclusion, the ceRNA interaction axis we identified is a potentially critical target for treating AD. Our results shed more lights on the possible pathogenic mechanism in AD using a lncRNA-associated ceRNA network.
| S-EPMC8495997 | biostudies-literature
Project description:Understanding the molecular pattern of fertility is considered as an important step in breeding of different species, and despite the high importance of the fertility, little success has been achieved in dissecting the interactome basis of sheep fertility. However, the complex mechanisms associated with prolificacy in sheep have not been fully understood. Therefore, this study aimed to use competitive endogenous RNA (ceRNA) networks to evaluate this trait to better understand the molecular mechanisms responsible for fertility. A competitive endogenous RNA (ceRNA) network of the corpus luteum was constructed between Romanov and Baluchi sheep breeds with either good or poor genetic merit for prolificacy using whole-transcriptome analysis. First, the main list of lncRNAs, miRNAs, and mRNA related to the corpus luteum that alter with the breed were extracted, then miRNA-mRNA and lncRNA-mRNA interactions were predicted, and the ceRNA network was constructed by integrating these interactions with the other gene regulatory networks and the protein-protein interaction (PPI). A total of 264 mRNAs, 14 lncRNAs, and 34 miRNAs were identified by combining the GO and KEGG enrichment analyses. In total, 44, 7, 7, and 6 mRNAs, lncRNAs, miRNAs, and crucial modules, respectively, were disclosed through clustering for the corpus luteum ceRNA network. All these RNAs involved in biological processes, namely proteolysis, actin cytoskeleton organization, immune system process, cell adhesion, cell differentiation, and lipid metabolic process, have an overexpression pattern (Padj < 0.01). This study increases our understanding of the contribution of different breed transcriptomes to phenotypic fertility differences and constructed a ceRNA network in sheep (Ovis aries) to provide insights into further research on the molecular mechanism and identify new biomarkers for genetic improvement.
| S-EPMC9332185 | biostudies-literature
Project description:BackgroundNumerous studies have highlighted that long non-coding RNAs (lncRNAs) can bind to microRNA (miRNA) sites as competing endogenous RNAs (ceRNAs), thereby affecting and regulating the expression of mRNAs and target genes. These lncRNA-associated ceRNAs have been theorized to play a significant role in cancer initiation and progression. However, the roles and functions of the lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of the tongue (SCCT) are still unclear.MethodsThe miRNA, mRNA and lncRNA expression profiles from 138 patients with SCCT were downloaded from The Cancer Genome Atlas database. We identified the differential expression of miRNAs, mRNAs, and lncRNAs using the limma package of R software. We used the clusterProfiler package for GO and KEGG pathway annotations. The survival package was used to estimate survival analysis according to the Kaplan-Meier curve. Finally, the GDCRNATools package was used to construct the lncRNA-miRNA-mRNA ceRNA network.ResultsIn total, 1943 SCCT-specific mRNAs, 107 lncRNAs and 100 miRNAs were explored. Ten mRNAs (CSRP2, CKS2, ADGRG6, MB21D1, GMNN, RIPOR3, RAD51, PCLAF, ORC1, NAGS), 9 lncRNAs (LINC02560, HOXC13 - AS, FOXD2 - AS1, AC105277.1, AC099850.3, STARD4 - AS1, SLC16A1 - AS1, MIR503HG, MIR100HG) and 8 miRNAs (miR - 654, miR - 503, miR - 450a, miR - 379, miR - 369, miR - 190a, miR - 101, and let-7c) were found to be significantly associated with overall survival (log-rank p < 0.05). Based on the analysis of the lncRNA-miRNA-mRNA ceRNA network, one differentially expressed (DE) lncRNA, five DEmiRNAs, and three DEmRNAs were demonstrated to be related to the pathogenesis of SCCT.ConclusionsIn this study, we described the gene regulation by the lncRNA-miRNA-mRNA ceRNA network in the progression of SCCT. We propose a new lncRNA-associated ceRNA that could help in the diagnosis and treatment of SCCT.
| S-EPMC6686570 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder in women of childbearing age. Recent studies suggest important roles for lncRNAs in PCOS development. Based on the hypothesis that lncRNAs are able to regulate mRNA functions by competitive binding to shared miRNAs, the present work sought to construct a PCOS-related lncRNA-mRNA network (PCLMN) to identify key lncRNAs with dysregulated expression and potential prognostic and therapeutic relevance. A global background network was constructed after retrieving lncRNA-miRNA and miRNA-mRNA pairs from the lncRNASNP2, miRTarBase and StarBase databases. Based on gene expression profiles from ovarian granulosa cells from PCOS patients and controls in the GEO's GSE95728 dataset, the PCLMN was then constructed by applying hypergeometric testing. Using topological analysis, we identified 3 lncRNAs (LINC00667, AC073172.1 and H19) ranking within the top-ten gene lists for all three centrality measures. We then explored their subcellular localization, performed functional module analyses, and identified 4 sex hormone-related transcription factors as potential regulators of their expression. Significant associations with inflammation, oxidative stress, and apoptosis-related processes and pathways were revealed for the key lncRNAs in our PCMLN. Further studies verifying the mRNA/lncRNA relationships identified herein are needed to clarify their clinical significance.
| S-EPMC8034915 | biostudies-literature