Identification and validation of a miRNA-based prognostic signature for cervical cancer through an integrated bioinformatics approach
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ABSTRACT:
SUBMITTER: Qi Y
PROVIDER: S-EPMC7747620 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Cervical cancer is one of the most common causes of cancer deaths in women due to poor prognosis and high mortality rates. A novel mRNA-miRNA-lncRNA signature linked to prognosis of cervical cancer is needed to help clinicians judge the prognosis of individual patients more accurately. On the basis of GEO datasets, a total of 161 upregulated and 242 downregulated DE-mRNAs were identified firstly. Among them, eight potential biomarkers were found to have prognostic values with cervical cancer and miRNAs-lncRNAs related to these biomarkers were then analyzed to create mRNA-miRNA-lncRNA networks in cervical cancer. Moreover, in vitro experiments such as qRT-PCR, western blot and Edu assays were also performed to validate these promising targets. On the basis of these findings, a total of eight mRNA-miRNA-lncRNA subnetworks were finally established as a novel mRNA-miRNA-lncRNA signature and independent prognostic indicator of clinically relevant parameters by ROC analysis, univariate and multivariate Cox regression. Since some work of validation was done, it is believed that this mRNA-miRNA-lncRNA prognostic signature may be applied as a potential clinical judgment to estimate the prognosis of cervical cancer.
| S-EPMC8806317 | biostudies-literature
Project description:BackgroundPhosphatidylinositol binding clathrin assembly protein interacting mitotic regulator (PIMREG) expression is upregulated in a variety of cancers. However, its potential role in breast cancer (BC) remains uncertain.MethodsThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to gather relevant information. The expression of PIMREG and its clinical implication in BC were assessed by using Wilcoxon rank-sum test. The prognostic value of PIMREG in BC was evaluated through the Cox regression model and nomogram, and visualized by Kaplan-Meier survival curves. Genes/proteins that interact with PIMREG in BC were also identified through GeneMANIA and MaxLink. Gene set enrichment analysis (GSEA) was then performed. The correlations of the immune cell infiltration and immune checkpoints with the expression of PIMREG in BC were explored via TIMER, TISIDB, and GEPIA. Potential drugs that interact with PIMREG in BC were explored via Q-omic. The siRNA transfection, CCK-8, and transwell migration assay were conducted to explore the function of PIMREG in cell proliferation and migration.ResultsPIMREG expression was significantly higher in infiltrating ductal carcinoma, estrogen receptor negative BC, and progestin receptor negative BC. High expression of PIMREG was associated with poor overall survival, disease-specific survival, and progression-free interval. A nomogram based on PIMREG was developed with a satisfactory prognostic value. PIMREG also had a high diagnostic ability, with an area under the curve of 0.940. Its correlations with several immunomodulators were also observed. Immune checkpoint CTLA-4 was significantly positively associated with PIMREG. HDAC2 was found as a potentially critical link between PIMREG and BRCA1/2. In addition, PIMREG knockdown could inhibit cell proliferation and migration in BC.ConclusionsThe high expression of PIMREG is associated with poor prognosis and immune checkpoints in BC. HDAC2 may be a critical link between PIMREG and BRCA1/2, potentially a therapeutic target.
| S-EPMC10358341 | biostudies-literature
Project description:The primary objective of this investigation was to determine the hub genes of hepatocellular carcinoma (HCC) through an in silico approach. In the current context of the increased incidence of liver cancers, this approach could be a useful prognostic biomarker and HCC prevention target. This study aimed to examine hub genes for immune cell infiltration and their good prognostic characteristics for HCC research. Human genes selected from databases (Gene Cards and DisGeNET) were used to identify the HCC markers. Further, classification of the hub genes from communicating genes was performed using data derived from the targets' protein-protein interaction (PPI) platform. The expression as well as survival studies of all these selected genes were validated by utilizing databases such as GEPIA2, HPA, and immune cell infiltration. Based on the studies, five hub genes (TP53, ESR1, AKT1, CASP3, and JUN) were identified, which have been linked to HCC. They may be an important prognostic biomarker and preventative target of HCC. In silico analysis revealed that out of five hub genes, the TP53 and ESR1 hub genes potentially act as key targets for HCC prevention and treatment.
| S-EPMC9646875 | biostudies-literature
Project description:OBJECTIVE:To date, The Cancer Genome Atlas (TCGA) has provided the most extensive molecular characterization of invasive cervical cancer (ICC). Analysis of reverse phase protein array (RPPA) data from TCGA samples showed that cervical cancers could be stratified into 3 clusters exhibiting significant differences in survival outcome: hormone, EMT, and PI3K/AKT. The goals of the current study were to: 1) validate the TCGA RPPA results in an independent cohort of ICC patients and 2) to develop and validate an algorithm encompassing a small antibody set for clinical utility. METHODS:Subjects consisted of 2 ICC patient cohorts with accompanying RPPA and clinical-pathologic data: 155 samples from TCGA (TCGA-155) and 61 additional, unique samples (MCW-61). Using data from 173 common RPPA antibodies, we replicated Silhouette clustering analysis in both ICC cohorts. Further, an index score for each patient was calculated from the survival-associated antibodies (SAAs) identified using Random survival forests (RSF) and the Cox proportional hazard regression model. Kaplan-Meier survival analysis and the log-rank test were performed to assess and compare cluster or risk group survival outcome. RESULTS:In addition to validating the prognostic ability of the proteomic clusters reported by TCGA, we developed an algorithm based on 22 unique antibodies (SAAs) that stratified women with ICC into low-, medium-, or high-risk survival groups. CONCLUSIONS:We provide a signature of 22 antibodies which accurately predicted survival outcome in 2 separate groups of ICC patients. Future studies examining these candidate biomarkers in additional ICC cohorts is warranted to fully determine their clinical potential.
| S-EPMC6825895 | biostudies-literature
Project description:BackgroundColon cancer is a worldwide leading cause of cancer-related mortality, and the prognosis of colon cancer is still needed to be improved. This study aimed to construct a prognostic model for predicting the prognosis of colon cancer.MethodsThe gene expression profile data of colon cancer were obtained from the TCGA, GSE44861, and GSE44076 datasets. The WGCNA module genes and common differentially expressed genes (DEGs) were used to screen out the prognosis-associated DEGs, which were used to construct a prognostic model. The performance of the prognostic model was assessed and validated in the TCGA training and microarray validation sets (GSE38832 and GSE17538). At last, the model and prognosis-associated clinical factors were used for the construction of the nomogram.ResultsFive colon cancer-related WGCNA modules (including 1160 genes) and 1153 DEGs between tumor and normal tissues were identified, inclusive of 556 overlapping DEGs. Stepwise Cox regression analyses identified there were 14 prognosis-associated DEGs, of which 12 DEGs were included in the optimized prognostic gene signature. This prognostic model presented a high forecast ability for the prognosis of colon cancer both in the TCGA training dataset and the validation datasets (GSE38832 and GSE17538; AUC > 0.8). In addition, patients' age, T classification, recurrence status, and prognostic risk score were associated with the prognosis of TCGA patients with colon cancer. The nomogram was constructed using the above factors, and the predictive 3- and 5-year survival probabilities had high compliance with the actual survival proportions.ConclusionsThe 12-gene signature prognostic model had a high predictive ability for the prognosis of colon cancer.
| S-EPMC7807455 | biostudies-literature
Project description:Background:Recurrence remains a major obstacle to long-term survival of laryngeal squamous cell carcinoma (LSCC). We conducted a genome-wide integrated analysis of methylation and the transcriptome to establish methylation-driven genes prognostic signature (MDGPS) to precisely predict recurrence probability and optimize therapeutic strategies for LSCC. Methods:LSCC DNA methylation datasets and RNA sequencing (RNA-seq) dataset were acquired from the Cancer Genome Atlas (TCGA). MethylMix was applied to detect DNA methylation-driven genes (MDGs). By univariate and multivariate Cox regression analyses, five genes of DNA MDGs was developed a recurrence-free survival (RFS)-related MDGPS. The predictive accuracy and clinical value of the MDGPS were evaluated by receiver operating characteristic (ROC) and decision curve analysis (DCA), and compared with TNM stage system. Additionally, prognostic value of MDGPS was validated by external Gene Expression Omnibus (GEO) database. According to 5 MDGs, the candidate small molecules for LSCC were screen out by the CMap database. To strengthen the bioinformatics analysis results, 30 pairs of clinical samples were evaluated by digoxigenin-labeled chromogenic in situ hybridization (CISH). Results:A total of 88 DNA MDGs were identified, and five RFS-related MDGs (LINC01354, CCDC8, PHYHD1, MAGEB2 and ZNF732) were chosen to construct a MDGPS. The MDGPS can effectively divide patients into high-risk and low-risk group, with the area under curve (AUC) of 0.738 (5-year RFS) and AUC of 0.74 (3-year RFS). Stratification analysis affirmed that the MDGPS was still a significant statistical prognostic model in subsets of patients with different clinical variables. Multivariate Cox regression analysis indicated the efficacy of MDGPS appears independent of other clinicopathological characteristics. In terms of predictive capacity and clinical usefulness, the MDGPS was superior to traditional TNM stage. Additionally, the MDGPS was confirmed in external LSCC cohorts from GEO. CMap matched the 9 most significant small molecules as promising therapeutic drugs to reverse the LSCC gene expression. Finally, CISH analysis in 30 LSCC tissues and paired adjacent normal tissues revealed that MAGEB2 has significantly higher expression of LSCC compared to adjacent non-neoplastic tissues; LINC01354, CCDC8, PHYHD1, and ZNF732 have significantly lower expression of LSCC compared to adjacent non-neoplastic tissues, which were in line with bioinformatics analysis results. Conclusion:A MDGPS, with five DNA MDGs, was identified and validated in LSCC patients by combining transcriptome and methylation datasets analysis. Compared TNM stage alone, it generates more accurate estimations of the recurrence prediction and maybe offer novel research directions and prospects for individualized treatment of patients with LSCC.
| S-EPMC7526132 | biostudies-literature
Project description:BackgroundIdentification of more promising microRNAs (miRNAs) are being extensively studied with respect to colorectal cancer (CRC), since CRC is the leading cause of cancer deaths and most common malignant tumors worldwide. A series of colon cancer (CCa) samples from The Cancer Genome Atlas (TCGA) were analyzed to provide a new perspective into this field.MethodsThe expression of miRNAs, mRNAs and the clinical data of 437 CRC patients were downloaded from the TCGA database. The survival-related differentially expressed miRNAs (sDMIRs) and mRNAs were detected by COX regression analysis. The high-risk group and low-risk group were separated by the median risk score of the risk score model. The potential clinical characteristics of these sDMIRs were analyzed by R software. The potential molecular mechanisms of these sDMIRs were explored by computational biology. The expression levels of three sDMIRs were explored by qPCR in CRC samples.ResultsThree DMIRs (hsa-miR-21-3p, hsa-miR-194-3p and hsa-miR-891a-5p) correlated with the most remarkable prognostic values of CRC patients were selected to establish the risk score model (RSM) by univariate and multivariate COX regression analysis and the survival probability of the low-risk group was longer than that in the high-risk group. We detected the target genes of three sDMIRs and the potential molecular mechanisms of these sDMIRs. We further verified the high expression levels of hsa-miR-21-3p and hsa-miR-194-3p were associated with the early T-stages, while hsa-miR-891a-5p illustrated the reversed result.ConclusionOur study demonstrated three sDMIRs with significantly clinical values illustrated the potential predicting values in the prognosis of CRC patients. Our results may provide a new perspective for the diagnostic methods and treatment strategies in CRC patients.
| S-EPMC8386531 | biostudies-literature
Project description:BackgroundGastric carcinoma (GC) is one of the most aggressive primary digestive cancers. It has unsatisfactory therapeutic outcomes and is difficult to diagnose early.AimTo identify prognostic biomarkers for GC patients using comprehensive bioinformatics analyses.MethodsDifferentially expressed genes (DEGs) were screened using gene expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases for GC. Overlapping DEGs were analyzed using univariate and multivariate Cox regression analyses. A risk score model was then constructed and its prognostic value was validated utilizing an independent Gene Expression Omnibus dataset (GSE15459). Multiple databases were used to analyze each gene in the risk score model. High-risk score-associated pathways and therapeutic small molecule drugs were analyzed and predicted, respectively.ResultsA total of 95 overlapping DEGs were found and a nine-gene signature (COL8A1, CTHRC1, COL5A2, AADAC, MAMDC2, SERPINE1, MAOA, COL1A2, and FNDC1) was constructed for the GC prognosis prediction. Receiver operating characteristic curve performance in the training dataset (The Cancer Genome Atlas-stomach adenocarcinoma) and validation dataset (GSE15459) demonstrated a robust prognostic value of the risk score model. Multiple database analyses for each gene provided evidence to further understand the nine-gene signature. Gene set enrichment analysis showed that the high-risk group was enriched in multiple cancer-related pathways. Moreover, several new small molecule drugs for potential treatment of GC were identified.ConclusionThe nine-gene signature-derived risk score allows to predict GC prognosis and might prove useful for guiding therapeutic strategies for GC patients.
| S-EPMC7509999 | biostudies-literature
Project description:In recent years, the incidence and mortality of cervical cancer have increased worldwide. At the same time, increasing data have confirmed that miRNA-mRNA plays a positive or negative regulatory role in many cancers. This study attempted to screen effective miRNA-mRNA in the progression of cervical cancer, and to study the mechanism of miRNA-mRNA in the progression of cervical cancer. The expression profile data of GSE7410, GSE 63514, GSE 86100 and TCGA-CESC were downloaded, and 34 overlapping differentially expressed genes (22 up-regulated and 12 down-regulated) and 166 miRNAs (74 down-regulated and 92 up-regulated) were screened through limma package. Then, miR-197-3p/TYMS pairs were obtained by PPI, functional enrichment, Kaplan-Meier plotter analysis, Cox univariate and multivariate analysis, risk modeling, WGCNA, qPCR and dual-luciferase experiments. The results showed that TYMS was an independent prognostic factor of cervical cancer, and its expression level was negatively correlated with cervical cancer tissue grade (TMN), tumor grade, age, microsatellite stability and tumor mutation load, and positively correlated with methyl expression in DNMT1, DNMT2, DNMT3A and DNMT3B. Functional experiments showed that TYMS knockout could promote the proliferation, migration and invasion of HeLa cells and reduce apoptosis. Overexpression of TYMS showed the opposite trend, miR-197-3p was negatively correlated with the expression of TYMS. MiR-197-3p inhibitor reversed the effect of si-TYMS on the proliferation of HeLa cells. In conclusion, these results reveal that TYMS plays a very important role in the prognosis and progression of cervical cancer, and has the potential to be thought of as cervical cancer biomarkers. At the same time, miR-197-3p/TYMS axis can regulate the deterioration of cervical cancer cells, which lays a foundation for the molecular diagnosis and treatment of cervical cancer.
| S-EPMC8727538 | biostudies-literature
Project description:BackgroundmiRNAs and genes can serve as biomarkers for the prognosis and therapy of cervical tumors whose metastasis into lymph nodes is closely associated with disease progression and poor prognosis.MethodsR software and Bioconductor packages were employed to identify differentially expressed miRNAs (DEMs) from The Cancer Genome Atlas (TCGA) database. GEO2R detected differentially expressed genes (DEGs) in the GSE7410 dataset originating from the Gene Expression Omnibus (GEO). A Cox proportional hazard regression model was established to select prognostic miRNA biomarkers. Online tools such as TargetScan and miRDB predicted target genes, and overlapping DEGs and target genes were defined as consensus genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) function annotations were performed to discern the potential functions of consensus genes. STRING and Cytoscape screened key genes and constructed a regulatory network.ResultsA combination of four miRNAs (down-regulated miR-502 and miR-145, up-regulated miR-142 and miR-33b) was identified as an independent prognostic signature of cervical cancer. A total of 94 consensus genes were significantly enriched in 7 KEGG pathways and 19 GO function annotations including the cAMP signaling pathway, the plasma membrane, integral components of the plasma membrane, cell adhesion, etc. The module analysis suggested that CXCL12, IGF1, PTPRC CDH5, RAD51B, REV3L, and WDHD1 are key genes that significantly correlate with cervical cancer lymph node metastasis.ConclusionsThis study demonstrates that a four-miRNA signature can be a prognostic biomarker, and seven key genes are significantly associated with lymph node metastasis in cervical cancer patients. These miRNAs and key genes have the potential to be therapeutic targets for cervical cancer. Among them, two miRNAs (miR-502 and miR-33b) and two key genes (PTPRC and CDH5) were first reported to be potential novel biomarkers for cervical cancer. The current study further characterizes the progression of lymph node metastasis and mechanism of cervical tumors; therefore, it provides a novel diagnostic indicator and therapeutic targets for future clinical treatments.
| S-EPMC7226536 | biostudies-literature