Novel lncRNA Panel as for Prognosis in Esophageal Squamous Cell Carcinoma Based on ceRNA Network Mechanism.
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ABSTRACT: Background
The competitive endogenous RNA (ceRNA) mechanism has been discovered recently and regulating cancer-related gene expressions. The ceRNA network participates in multiple processes, such as cell proliferation and metastasis, and potentially drives the progression of cancer. In this study, we focus on the ceRNA networks of esophageal squamous cell carcinoma and discovered a novel biomarker panel for cancer prognosis.Methods
RNA expression data of esophageal carcinoma from the TCGA database were achieved and constructed ceRNA network in esophageal carcinoma using R packages.Results
Four miRNAs were discovered as the core of the ceRNA model, including miR-93, miR-191, miR-99b, and miR-3615. Moreover, we constructed a ceRNA network in esophageal carcinoma, which included 4 miRNAs and 6 lncRNAs. After ceRNA network modeling, we investigated six lncRNAs which could be taken together as a panel for prognosis prediction of esophageal cancer, including LINC02575, LINC01087, LINC01816, AL136162.1, AC012073.1, and AC117402.1. Finally, we tested the predictive power of the panel in all TCGA samples.Conclusions
Our study discovered a new biomarker panel which may have potential values in the prediction of prognosis of esophageal carcinoma.
SUBMITTER: Zhang J
PROVIDER: S-EPMC8486540 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC7780331 | biostudies-literature
Project description:BackgroundThe competing endogenous RNA (ceRNA) activity of circular RNAs (circRNAs) has been implicated in the pathogenesis of cancers, including esophageal squamous cell carcinoma (ESCC). Here, we identified the ceRNA mechanism of circ_0000654 regulation in ESCC.MethodsThe levels of circ_0000654, E2F transcription factor 3 (E2F3), and microRNA (miR)-375 were gauged by quantitative real-time PCR (qRT-PCR) and western blot. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell apoptosis was detected by flow cytometry. Cell colony formation was tested by colony formation assay. Dual-luciferase reporter, RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to confirm the direct relationship between miR-375 and circ_0000654 or E2F3. Xenograft model assays were used to evaluate the effect of circ_0000654 in vivo.ResultsCirc_0000654 and E2F3 were upregulated in ESCC. Circ_0000654 depletion enhanced cell apoptosis and hindered cell proliferation and glycolysis in vitro, as well as weakened tumor growth in vivo. Increased expression of E2F3 counteracted the effects of circ_0000654 depletion. Mechanistically, E2F3 was a target of miR-375, and circ_0000654 modulated E2F3 expression through sequestering miR-375. Furthermore, miR-375 upregulation phenocopied circ_0000654 knockdown in inhibiting ESCC progression.ConclusionOur findings identify a new circ_0000654/miR-375/E2F3 ceRNA crosstalk for the oncogenic role of circ_0000654 in ESCC and establish a notion that targeting circ_0000654 and its pathways may have the potential to improve ESCC outcome.
| S-EPMC9346169 | biostudies-literature
Project description:A cutaneous squamous cell carcinoma (cSCC) derived from keratinocytes is the second most common cause of non-melanoma skin cancer. The accumulation of the mutational burden of genes and cellular DNA damage caused by the risk factors (e.g., exposure to ultraviolet radiation) contribute to the aberrant proliferation of keratinocytes and the formation of a cSCC. A cSCC encompasses a spectrum of diseases that range from recursor actinic keratosis (AK) and squamous cell carcinoma (SCC) in situ (SCCIS) to invasive cSCCs and further metastatic SCCs. Emerging evidence has revealed that lncRNAs are involved in the biological process of a cSCC. According to the ceRNA regulatory theory, lncRNAs act as natural miRNA sponges and interact with miRNA response elements, thereby regulating the mRNA expression of their down-stream targets. This study was designed to search for the potential lncRNAs that may become potential therapeutic targets or biomarkers of a cSCC. Considering the spirit of the study to be adequately justified, we collected microarray-based datasets of 19 cSCC tissues and 12 normal skin samples from the GEO database (GSE42677 and GSE45164). After screening the differentially expressed genes via a limma package, we identified 24 differentially expressed lncRNAs (DElncRNAs) and 3221 differentially expressed mRNAs (DEmRNAs). The miRcode, miRTarBase, miRDB and TargetScan databases were used to predict miRNAs that could interact with DElncRNAs and DEmRNAs. A total of 137 miRNA-lncRNA and 221 miRNA-mRNA pairs were retained in the ceRNA network, consisting of 31 miRNAs, 11 DElncRNAs and 155 DEmRNAs. For the functional analysis, the top enriched biological process was enhancer sequence-specific DNA binding in Gene Ontology (GO) terms. The FoxO signaling pathway, autophagy and cellular senescence were the top enrichment terms based on a Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The combination of a STRING tool and Cytoscape software (plug-in MCODE) identified five core mRNAs and built a core mRNA-associated ceRNA network. The expression for five identified core mRNAs and their related nine lncRNAs was validated using the external dataset GSE7553. Finally, one lncRNA HLA-F-AS1 and three mRNAs named AGO4, E2F1 and CCND1 were validated with the same expression patterns. We speculate that lncRNA HLA-F-AS1 may sponge miR-17-5p or miR-20b-5p to regulate the expression of CCND1 and E2F1 in the cSCC. The present study may provide potential diagnostic and therapeutic targets for cSCC patients.
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Project description:Esophageal squamous cell carcinoma (ESCC) is a common cancer with poor prognosis. In order to identify useful biomarkers for accurately classifying prognostic risks for ESCC patients, we examined the expression of six proteins by immunohistochemistry (IHC) in 590 paraffin-embedded ESCC samples. The candidate proteins include p53, EGFR, c-KIT, TIMP1 and PI3K-p110α reported to be altered in ESCC tissues as well as another important component of PI3K, PI3K-p85α. Of the six proteins tested, p53, EGFR, c-KIT, TIMP1 and PI3K-p85α were detected with high expression in 43.0%, 36.6%, 55.9%, 70.7% and 57.1% of tumors, respectively. Significant associations were found between high expression of PI3K-p85α, EGFR and p53 and poor prognosis (P = 0.00111; 0.00001; 0.00426). Applying these three proteins as an IHC panel could divide patients into different subgroups (P<0.000001). Multivariate cox regression analysis indicated that the three-protein panel was an independent prognostic factor with very high statistical significance (HR = 2.090, 95% CI: 1.621-2.696, P = 0.00000001). The data suggest that the three-protein panel of PI3K-p85α, EGFR and p53 is an important candidate biomarker for the prognosis of patients with ESCC.
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Project description:Long non-coding RNAs (lncRNAs) have emerged as useful prognostic markers in many tumors. In this study, we investigated the potential application of lncRNA markers for the prognostic prediction of esophageal squamous cell carcinoma (ESCC). We identified ESCC-associated lncRNAs by comparing ESCC tissues with normal tissues. Subsequently, Kaplan-Meier (KM) method in combination with the univariate Cox proportional hazards regression (UniCox) method was used to screen prognostic lncRNAs. By combining the differential and prognostic lncRNAs, we developed a prognostic model using cox stepwise regression analysis. The obtained prognostic prediction model could effectively predict the 3- and 5-year prognosis and survival of ESCC patients by time-dependent receiver operating characteristic (ROC) curves (area under curve = 0.87 and 0.89, respectively). Besides, a lncRNA-based classification of ESCC was generated using k-mean clustering method and we obtained two clusters of ESCC patients with association with race and Barrett's esophagus (BE) (both P < 0.001). Finally, we found that lncRNA AC007128.1 was upregulated in both ESCC cells and tissues and associated with poor prognosis of ESCC patients. Furthermore, AC007128.1 could promote epithelial-mesenchymal transition (EMT) of ESCC cells by increasing the activation of MAPK/ERK and MAPK/p38 signaling pathways. Collectively, our findings indicated the potentials of lncRNA markers in the prognosis, molecular subtyping, and EMT of ESCC.
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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:Liver cancer is a highly malignant tumor. Notably, recent studies have found that long non-coding RNAs (lncRNAs) play a prominent role in the prognosis of patients with liver cancer. Herein, we attempted to construct an lncRNA model to accurately predict the survival rate in liver cancer. Based on The Cancer Genome Atlas (TCGA) database, we first identified 1066 lncRNAs with differential expression. The patient data obtained from TCGA were divided into the experimental group and the verification group. According to the difference in lncRNAs, we used single-factor and multi-factor Cox regression to select the genes needed to build the model in the experimental group, which were verified in the verification group. The results showed that the model could accurately predict the survival rate of patients in the high and low risk groups. The reliability of the model was also confirmed by the area under the receiver operating characteristic curve. Our model is significantly correlated with different clinicopathological features. Finally, we built a ceRNA network based on lncRNAs, which was used to display miRNAs and mRNAs related to lncRNAs. In summary, we constructed an lncRNA model to predict the survival rate of patients with hepatocellular carcinoma.
| S-EPMC8633432 | biostudies-literature
Project description:Accumulating evidence indicates that lncRNAs can interact with miRNAs to regulate target mRNAs through competitive interactions. However, this mechanism remains largely unexplored in laryngeal squamous cell carcinoma (LSCC). In this study, transcriptome-wide RNA sequencing was performed on 3 pairs of LSCC tissues and adjacent normal tissues to investigate the expression profiles of lncRNAs, miRNAs and mRNAs, with differential expression of 171 lncRNAs, 36 miRNAs and 1709 mRNAs detected. Seven lncRNAs, eight mRNAs and three miRNAs were identified to be dysregulated in patients' tissues by using qRT-PCR. GO and KEGG pathway enrichment analyses were performed to elucidate the potential functions of these differentially expressed genes in LSCC. Subsequently, a ceRNA (lncRNA-miRNA-mRNA) network including 4631 ceRNA pairs was constructed based on predicted miRNAs shared by lncRNAs and mRNAs. Cis- and transregulatory lncRNAs were analysed by bioinformatics-based methods. Importantly, mRNA-related ceRNA networks (mRCNs) were further obtained based on potential cancer-related coding genes. Coexpression between lncRNAs and downstream mRNAs was used as a criterion for the validation of mRCNs, with the ZNF561-AS1-miR217-WNT5A and SATB1-AS1-miR1299-SAV1/CCNG2/SH3 KBP1/JADE1/HIPK2 ceRNA regulatory interactions determined, followed by experimental validation after siRNA transfection. Moreover, ceRNA activity analysis revealed that different activities of ceRNA modules existing in specific pathological environments may contribute to the tumorigenesis of LSCC. Consistently, both downregulated SATB1-AS1 and ZNF561-AS1 significantly promoted laryngeal cancer cell migration and invasion, indicating their important roles in LSCC via a ceRNA regulatory mechanism. Taken together, the results of this investigation uncovered and systemically characterized a lncRNA-related ceRNA regulatory network that may be valuable for the diagnosis and treatment of LSCC.
| S-EPMC7549682 | biostudies-literature
Project description:BackgroundCircular RNAs (circRNAs) can function as competing endogenous RNAs (ceRNAs) to impact the development of esophageal squamous cell cancer (ESCC). Human circ_0001946 has been identified as a potential anticancer factor in ESCC, yet our understanding of its molecular basis remains limited.MethodsCirc_0001946, microRNA (miR)-1290 and SRY-box transcription factor 6 (SOX6) were quantified by quantitative reasl-time PCR (qRT-PCR) or immunoblotting. Cell proliferation was assessed by CCK-8 and EDU assays. Cell apoptosis and invasion were evaluated by flow cytometry and transwell assays, respectively. Cell migration was detected by transwell and wound-healing assays. The direct relationship between miR-1290 and circ_0001946 or SOX6 was determined by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenograft model assays were used to assess the role of circ_0001946 in tumor growth.ResultsCirc_0001946 expression was attenuated in human ESCC, and circ_0001946 increase impeded cell proliferation, invasion, migration and enhanced apoptosis in vitro. Moreover, circ_0001946 increase diminished xenograft growth in vivo. Mechanistically, circ_0001946 bound to miR-1290, and re-expression of miR-1290 reversed circ_0001946-dependent cell properties. SOX6 was a miR-1290 target and it was responsible for the regulation of miR-1290 in cell properties. Furthermore, circ_0001946 functioned as a ceRNA to regulate SOX6 expression via miR-1290.ConclusionOur findings uncover an undescribed molecular mechanism, the circ_0001946/miR-1290/SOX6 ceRNA crosstalk, for the anti-ESCC activity of circ_0001946.
| S-EPMC9058308 | biostudies-literature
Project description:AC007128.1, a long non-coding RNA, was upregulated in both ESCC tissues and cells, and associated with poor prognosis in ESCC. AC007128.1 can promote migration and invasion in ESCC cell lines. By RNA-sequencing analysis, we observed the significant changes of genes important in AC007128.1-depleted cells. We generated two KYSE150 cell lines stably transduced with either a sh-NC lentiviral construct or a shRNA lentiviral construct designed to target AC007128.1 RNA to investigate the consequences on the gene expression profile of AC007128.1 knockdown in KYSE150 cells.
2021-02-24 | GSE167345 | GEO