Integral Analyses of Competing Endogenous RNA Mechanisms and DNA Methylation Reveal Regulatory Mechanisms in Osteosarcoma.
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ABSTRACT:
SUBMITTER: Wu T
PROVIDER: S-EPMC8696003 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most common and deadly malignant tumors, with a high rate of recurrence worldwide. This study aimed to investigate the mechanism underlying the progression of HCC and to identify recurrence-related biomarkers.MethodsWe first analyzed 132 HCC patients with paired tumor and adjacent normal tissue samples from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). The expression profiles and clinical information of 372 HCC patients from The Cancer Genome Atlas (TCGA) database were next analyzed to further validate the DEGs, construct competing endogenous RNA (ceRNA) networks and discover the prognostic genes associated with recurrence. Finally, several recurrence-related genes were evaluated in two external cohorts, consisting of fifty-two and forty-nine HCC patients, respectively.ResultsWith the comprehensive strategies of data mining, two potential interactive ceRNA networks were constructed based on the competitive relationships of the ceRNA hypothesis. The 'upregulated' ceRNA network consists of 6 upregulated lncRNAs, 3 downregulated miRNAs and 5 upregulated mRNAs, and the 'downregulated' network includes 4 downregulated lncRNAs, 12 upregulated miRNAs and 67 downregulated mRNAs. Survival analysis of the genes in the ceRNA networks demonstrated that 20 mRNAs were significantly associated with recurrence-free survival (RFS). Based on the prognostic mRNAs, a four-gene signature (ADH4, DNASE1L3, HGFAC and MELK) was established with the least absolute shrinkage and selection operator (LASSO) algorithm to predict the RFS of HCC patients, the performance of which was evaluated by receiver operating characteristic curves. The signature was also validated in two external cohort and displayed effective discrimination and prediction for the RFS of HCC patients.ConclusionsIn conclusion, the present study elucidated the underlying mechanisms of tumorigenesis and progression, provided two visualized ceRNA networks and successfully identified several potential biomarkers for HCC recurrence prediction and targeted therapies.
| S-EPMC8058997 | biostudies-literature
Project description:The present study aimed to screen all types of RNAs involved in the development of papillary thyroid carcinoma (PTC). RNA?sequencing data of PTC and normal samples were used for screening differentially expressed (DE) microRNAs (DE?miRNAs), long non?coding RNAs (DE?lncRNAs) and genes (DEGs). Subsequently, lncRNA?miRNA, miRNA?gene (that is, miRNA?mRNA) and gene?gene interaction pairs were extracted and used to construct regulatory networks. Feature genes in the miRNA?mRNA network were identified by topological analysis and recursive feature elimination analysis. A support vector machine (SVM) classifier was built using 15 feature genes, and its classification effect was validated using two microarray data sets that were downloaded from the Gene Expression Omnibus (GEO) database. In addition, Gene Ontology function and Kyoto Encyclopedia Genes and Genomes pathway enrichment analyses were conducted for genes identified in the ceRNA network. A total of 506 samples, including 447 tumor samples and 59 normal samples, were obtained from The Cancer Genome Atlas (TCGA); 16 DE?lncRNAs, 917 DEGs and 30 DE?miRNAs were screened. The miRNA?mRNA regulatory network comprised 353 nodes and 577 interactions. From these data, 15 feature genes with high predictive precision (>95%) were extracted from the network and were used to form an SVM classifier with an accuracy of 96.05% (486/506) for PTC samples downloaded from TCGA, and accuracies of 96.81 and 98.46% for GEO downloaded data sets. The ceRNA regulatory network comprised 596 lines (or interactions) and 365 nodes. Genes in the ceRNA network were significantly enriched in 'neuron development', 'differentiation', 'neuroactive ligand?receptor interaction', 'metabolism of xenobiotics by cytochrome P450', 'drug metabolism' and 'cytokine?cytokine receptor interaction' pathways. Hox transcript antisense RNA, miRNA?206 and kallikrein?related peptidase 10 were nodes in the ceRNA regulatory network of the selected feature gene, and they may serve import roles in the development of PTC.
| S-EPMC6059698 | biostudies-literature
Project description:The etiology of osteosarcoma (OS) is complex and not fully understood till now. This study aimed to identify the miRNAs, circRNAs, and genes (mRNAs) that are differentially expressed in OS cell lines to investigate the mechanism of circRNA-associated competing endogenous RNAs (ceRNAs) in OS. Microarray datasets reporting mRNA (GSE70414), miRNA (GSE70367), and circRNA changes (GSE96964) in human OS cell lines were downloaded, differentially expressed (DE) RNAs were identified, and DEmRNAs were used for the annotation of Gene Ontology (GO) biological processes (BP), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The mechanisms of DEcircRNA-mediated ceRNAs were identified in a step-by-step process. A total of 326 DEmRNAs, 45 DEmiRNAs, and 110 DEcircRNAs were identified from 3 datasets. The DEmRNAs were associated with GO BP terms, including cholesterol biosynthetic process, angiogenesis, extracellular matrix organization and KEGG pathways, including p53 signaling pathway and biosynthesis of antibiotics. The final ceRNA network consisted of 8 DEcircRNAs, including 5 pappalysin (PAPPA) 1-derived DEcircRNAs (hsa_circ_0005456, hsa_circ_0088209, hsa_circ_0002052, hsa_circ_0088214 and has_circ_0008792, all downregulated), 3 DEmiRNAs (hsa-miR-760, hsa-miR-4665-5p and hsa-miR-4539, all upregulated), and downregulated genes (including MMP13 and HMOX1). The ceRNA regulation network of OS was built, which played important roles in the pathogenesis of OS and might be of great importance in therapy.
| S-EPMC8544760 | biostudies-literature
Project description:BackgroundOsteosarcoma is the primary bone malignant neoplasm that often develops metastasis. Increasing evidences have shown that non-coding RNAs (ncRNAs) relate to the progression of osteosarcoma. However, the ncRNAs' roles in osteosarcoma metastasis are still unknown.MethodsDifferentially expressed (DE) RNAs were identified from Gene Expression Omnibus (GEO) database. Protein-protein interaction (PPI) of DE messenger RNAs (DEmRNAs) was built through STRING database. The target mRNAs and long ncRNAs (lncRNAs) of microRNAs (miRNA) were predicted through miRDB, Targetscan and Genecode databases, which then cross-checked with previously obtained DERNAs to construct competing endogenous RNA (ceRNA) network. All networks were visualized via Cytoscape and the hub RNAs were screened out through Cytoscape plug-in Cytohubba. The gene functional and pathway analyses were performed through DAVID and MirPath databases. The survival analyses of hub RNAs were obtained through Kaplan-Meier (KM) survival curves.ResultsFive hundred sixty-four DEmRNAs, 16 DElncRNAs and 22 DEmiRNAs were screened out. GO functional and KEGG pathway analyses showed that DERNAs were significantly associated with tumor metastasis. The ceRNA network including 6 lncRNAs, 55 mRNAs and 20 miRNAs were constructed and the top 10 hub RNAs were obtained. Above all, PI3K/AKT signaling pathway was identified as the most important osteosarcoma metastasis-associated pathway and its hub ceRNA module was constructed. The survival analyses showed that the RNAs in hub ceRNA module closely related to osteosarcoma patients' prognosis.ConclusionsThe current study provided a new perspective on osteosarcoma metastasis. More importantly, the RNAs in hub ceRNA module might act as the novel therapeutic targets and prognostic factors for osteosarcoma patients.
| S-EPMC7887822 | biostudies-literature
Project description:This study aimed to characterize circular RNA (circRNA) expression profiles and biological functions in head and neck squamous cell carcinoma (HNSCC). Differentially expressed circRNAs were screened using an Arraystar Human CircRNA Array and verified by reverse transcription-quantitative polymerase chain reaction. Multiple bioinformatics methods and a hypergeometric test were employed to predict the interactions between RNAs and the functional circRNA?microRNA (miRNA)-mRNA axes in HNSCC. As a result, 287 circRNAs and 1,053 mRNAs were determined to be differentially expressed in HNSCC compared with the adjacent tissue. In addition, the expression levels of circRNA_036186 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, ? polypeptide (14?3?3?) were identified to be significantly different. A competing endogenous RNA (ceRNA) network was constructed, consisting of 5 circRNAs, 385 miRNAs and 96 mRNAs. Furthermore, we predicted that miR?193b?3p exerts a significant effect on 14?3?3?, and was significantly associated with the Hippo signaling pathway in HNSCC. On the whole, these findings suggest that circRNA_036186 likely regulates 14?3?3? expression by functioning as a ceRNA in the development and progression of HNSCC.
| S-EPMC6086620 | biostudies-literature
Project description:Osteosarcoma (OS) is one of the most common types of primary bone tumors in early adolescence with unsatisfied prognosis. Aberrant DNA methylation had been demonstrated to be related to tumorigenesis and progression of multiple cancers and could serve as the potential biomarkers for the prognosis of human cancers. In conclusion, this study identified 18 downregulated hypomethylation genes and 52 upregulated hypomethylation genes in OS by integrating the analysis the GSE97529 and GSE42572 datasets. Bioinformatics analysis revealed that OS-specific methylated genes were involved in regulating multiple biological processes, including chemical synaptic transmission, transcription, response to drug, and regulating immune response. KEGG pathway analysis showed that OS-specific methylated genes were associated with the regulation of Hippo, cAMP calcium, MAPK, and Wnt signaling pathways. By analyzing R2 datasets, this study showed that the dysregulation of these OS-specific methylated genes was associated with the metastasis-free survival time in patients with OS, including CBLN4, ANKMY1, BZW1, KRTCAP3, GZMB, KRTDAP, LY9, PFKFB2, PTPN22, and CLDN7. This study provided a better understanding of the molecular mechanisms underlying the progression and OS and novel biomarkers for the prognosis of OS.
| S-EPMC7443031 | biostudies-literature
Project description:MicroRNAs (miRNAs) are small RNA molecules, about 22 nucleotide long, which post-transcriptionally regulate their target messenger RNAs (mRNAs). They accomplish key roles in gene regulatory networks, ranging from signaling pathways to tissue morphogenesis, and their aberrant behavior is often associated with the development of various diseases. Recently it has been experimentally shown that the way miRNAs interact with their targets can be described in terms of a titration mechanism. From a theoretical point of view titration mechanisms are characterized by threshold effect at near-equimolarity of the different chemical species, hypersensitivity of the system around the threshold, and cross-talk among targets. The latter characteristic has been lately identified as competing endogenous RNA (ceRNA) effect to mark those indirect interactions among targets of a common pool of miRNAs they are in competition for. Here we propose a stochastic model to analyze the equilibrium and out-of-equilibrium properties of a network of [Formula: see text] miRNAs interacting with [Formula: see text] mRNA targets. In particular we are able to describe in detail the peculiar equilibrium and non-equilibrium phenomena that the system displays in proximity to the threshold: (i) maximal cross-talk and correlation between targets, (ii) robustness of ceRNA effect with respect to the model's parameters and in particular to the catalyticity of the miRNA-mRNA interaction, and (iii) anomalous response-time to external perturbations.
| S-EPMC3694070 | biostudies-literature
Project description:Coronary heart disease (CHD) is a global health concern, and its molecular origin is not fully elucidated. Dysregulation of ncRNAs has been linked to many metabolic and infectious diseases. This study aimed to explore the role of circRNAs in the pathogenesis of CHD and predicted a candidate circRNA that could be targeted for therapeutic approaches to the disease. circRNAs associated with CHD were identified and CHD gene expression profiles were obtained, and analyzed with GEO2R. In addition, differentially expressed miRNA target genes (miR-DEGs) were identified and subjected to functional enrichment analysis. Networks of circRNA/miRNA/mRNA and the miRNA/affected pathways were constructed. Furthermore, a miRNA/mRNA homology study was performed. We identified that hsa_circ_0126672 was strongly associated with the CHD pathology by competing for endogenous RNA (ceRNA) mechanisms. hsa_circ_0126672 characteristically sponges miR-145-5p, miR-186-5p, miR-548c-3p, miR-7-5p, miR-495-3p, miR-203a-3p, and miR-21. Up-regulation of has_circ_0126672 affected various CHD-related cellular functions, such as atherosclerosis, JAK/STAT, and Apelin signaling pathways. Our results also revealed a perfect and stable interaction for the hybrid of miR-145-5p with NOS1 and RPS6KB1. Finally, miR-145-5p had the highest degree of interaction with the validated small molecules. Henchashsa_circ_0126672 and target miRNAs, notably miR-145-5p, could be good candidates for the diagnosis and therapeutic approaches to CHD.
| S-EPMC10047999 | biostudies-literature
Project description:Chemo-resistance is a huge obstacle encountered in the osteosarcoma (OS) treatment. Protein-coding mRNAs, as well as non-coding RNAs (ncRNAs), including long ncRNA (lncRNA), circular RNA (circRNA), and microRNA (miRNA), have been demonstrated to play an essential role in the regulation of cancer biology. However, the comprehensive expression profile and competing endogenous RNA (ceRNA) regulatory network between mRNAs and ncRNAs in the OS chemo-resistance still remain unclear. In the current study, we developed whole-transcriptome sequencing (RNA sequencing [RNA-seq]) in the three paired multi-drug chemo-resistant and chemo-sensitive OS cell lines to comprehensively identify differentially expressed lncRNAs, circRNAs, miRNAs, and mRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for mRNAs with significantly different expression. Then the ceRNA networks combining lncRNAs, circRNAs, miRNAs, and mRNAs were predicted and constructed on the basis of the authoritative miRanda and TargetScan databases combined with the widely accepted vital drug resistance-related genes and signal transduction pathways. In addition, two constructed ceRNA regulatory pathways, lncRNAMEG3/hsa-miR-200b-3p/AKT2 and hsa_circ_0001258/hsa-miR-744-3p/GSTM2, were randomly selected and validated by real-time qPCR, RNA immunoprecipitation (RIP), RNA pull-down assay, and dual luciferase reporter gene system. Taken together, our findings may provide new evidence for the underlying mechanism of OS chemo-resistance and uncover some novel targets for reversing it.
| S-EPMC6401193 | biostudies-literature
Project description:BackgroundPancreatic cancer is an insidious and heterogeneous malignancy with poor prognosis that is often locally unresectable. Therefore, determining the underlying mechanisms and effective prognostic indicators of pancreatic cancer may help optimize clinical management. This study was conducted to develop a prognostic model for pancreatic cancer based on a competing endogenous RNA (ceRNA) network.MethodsWe obtained transcriptomic data and corresponding clinicopathological information of pancreatic cancer samples from The Cancer Genome Atlas (TCGA) database (training set). Based on the ceRNA interaction network, we screened candidate genes to build prediction models. Univariate Cox regression analysis was performed to screen for genes associated with prognosis, and least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to construct a predictive model. A receiver operating characteristic (ROC) curve was drawn, and the C-index was calculated to evaluate the accuracy of the prediction model. Furthermore, we downloaded transcriptomic data and related clinical information of pancreatic cancer samples from the Gene Expression Omnibus database (validation set) to evaluate the robustness of our prediction model.ResultsEight genes (ANLN, FHDC1, LY6D, SMAD6, ACKR4, RAB27B, AUNIP, and GPRIN3) were used to construct the prediction model, which was confirmed as an independent predictor for evaluating the prognosis of patients with pancreatic cancer through univariate and multivariate Cox regression analysis. By plotting the decision curve, we found that the risk score model is an independent predictor has the greatest impact on survival compared to pathological stage and targeted molecular therapy.ConclusionsAn eight-gene prediction model was constructed for effectively and independently predicting the prognosis of patients with pancreatic cancer. These eight genes identified show potential as diagnostic and therapeutic targets.
| S-EPMC9745361 | biostudies-literature