Expression profile of epithelial-mesenchymal transition-related genes as a prognostic biomarker for endometrial cancer
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ABSTRACT:
SUBMITTER: Ye L
PROVIDER: S-EPMC8489121 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesThe epithelial-mesenchymal-transition (EMT) is an important step in the invasion and metastasis of cancer. A critical molecular feature of this process is the downregulation of E-cadherin expression, which is mainly controlled by Snail-related zinc-finger transcription factors (Snail and Slug). The aim of this study was to evaluate the prognostic impact of EMT-related protein (E-cadherin, Snail and Slug) expression in endometrial cancer.MethodsAn immunohistochemical analysis was conducted using tissue microarray samples of 354 primary tumors and 30 metastases of endometrial carcinomas, and the relationship between protein expression, clinicopathological features and outcomes were investigated.ResultsReduced E-cadherin was seen in 39.8% of primary tumors. Reduced E-cadherin was seen in 19.5%, 40.8% and 72.7% of G₁, G₂ and G₃ endometrioid adenocarcinomas, respectively. The nuclear expression of Snail and Slug were positive in 16.9% and 3.7% of primary tumors, respectively. EMT status, which was represented by both reduced E-cadherin and nuclear expression of Snail, was significantly associated with histological type, FIGO stage, myometrial invasion, positive peritoneal cytology and patient survival (p < 0.01). There was no difference in the rates of EMT status between the primary tumors and metastases. A multivariate analysis showed that EMT-positive status was a significant predictor for both the progression-free survival and overall survival (p < 0.01).ConclusionsThese data indicate that EMT status has a prognostic impact in endometrial cancer. Therefore, the clarification and control of EMT signaling is a promising molecular targeting therapy in endometrial cancer.
| S-EPMC3566047 | biostudies-literature
Project description:BackgroundsEpithelial-mesenchymal transition (EMT) is a sequential process where tumor cells develop from the epithelial state to the mesenchymal state. EMT contributes to various tumor functions including initiation, propagating potential, and resistance to therapy, thus affecting the survival time of patients. The aim of this research is to set up an EMT-related prognostic signature for endometrial cancer (EC).MethodsEMT-related gene (ERG) expression and clinical data were acquired from The Cancer Genome Atlas (TCGA). The entire set was randomly divided into two sets, one for contributing the risk model (risk score) and the other for validating. Univariate and multivariate Cox proportional hazards regression analyses were applied to the training set to select the prognostic ERGs. The expression of 10 ERGs was confirmed by qRT-PCR in clinical samples. Then, we developed a nomogram predicting 1-/3-/5-year survival possibility combining the risk score and clinical factors. The entire set was stratified into the high- and low-risk groups, which was used to analyze the immune infiltrating, tumorigenesis pathways, and response to drugs.ResultsA total of 220 genes were screened out from 1,316 ERGs for their differential expression in tumor versus normal. Next, 10 genes were found to be associated with overall survival (OS) in EC, and the expression was validated by qRT-PCR using clinical samples, so we constructed a 10-ERG-based risk score to distinguish high-/low-risk patients and a nomogram to predict survival rate. The calibration plots proved the predictive value of our model. Gene Set Enrichment Analysis (GSEA) discovered that in the low-risk group, immune-related pathways were enriched; in the high-risk group, tumorigenesis pathways were enriched. The low-risk group showed more immune activities, higher tumor mutational burden (TMB), and higher CTAL4/PD1 expression, which was in line with a better response to immune checkpoint inhibitors. Nevertheless, response to chemotherapeutic drugs turned out better in the high-risk group. The high-risk group had higher N 6-methyladenosine (m6A) RNA expression, microsatellite instability level, and stemness indices.ConclusionWe constructed the ERG-related signature model to predict the prognosis of EC patients. What is more, it might offer a reference for predicting individualized response to immune checkpoint inhibitors and chemotherapeutic drugs.
| S-EPMC8795518 | biostudies-literature
Project description:TET3 is a member of the TET (ten-eleven translocation) proteins family that catalyzes the conversion of the 5-methylcytosine into 5-hydroxymethylcytosine. TET proteins can also affect chromatin modifications and gene expression independently of their enzymatic activity via interactions with other proteins. O-GlcNAc transferase (OGT), the enzyme responsible for modification of proteins via binding of N-acetylglucosamine residues, is one of the proteins whose action may be dependent on TET3. Here, we demonstrated that in endometrial cancer cells both TET3 and OGT affected the expression of genes involved in epithelial to mesenchymal transition (EMT), i.e., FOXC1, TWIST1, and ZEB1. OGT overexpression was caused by an increase in TWIST1 and ZEB1 levels in HEC-1A and Ishikawa cells, which was associated with increased O-GlcNAcylation of histone H2B and trimethylation of H3K4. The TET3 had the opposite effect on gene expressions and histone modifications. OGT and TET3 differently affected FOXC1 expression and the migratory potential of HEC-1A and Ishikawa cells. Analysis of gene expressions in cancer tissue samples from endometrial cancer patients confirmed the association between OGT or TET3 and EMT genes. Our results contribute to the knowledge of the role of the TET3/OGT relationship in the complex mechanism supporting endometrial cancer progression.
| S-EPMC8708691 | biostudies-literature
Project description:Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. The aim of this study was to analyze the expression of SNAIL, SLUG, TWIST1, TWIST2, ZEB1, and ZEB 2 in primary tumor and the correlation with morphological and clinical characteristics of EC. The study included 158 patients with EC after surgical treatments: total hysterectomy and lymphadenectomy. The percentages of EC specimens testing positively for the EMT transcription factors were 84.5% for SNAIL, 92.2% for SLUG, 10.9% for TWIST1, 100% for TWIST2, 89% for ZEB1, and 98% for ZEB2. The expression of SLUG in patients with FIGO stage III or IV, type II EC, myometrial invasion ? 50% of the uterine wall thickness, and adnexal involvement and in patients with distant metastases was significantly higher. SLUG and ZEB2 expressions were identified as significant predictors of higher FIGO stages (III or IV) on univariate analysis. The overexpression of SLUG was a significant predictor of more aggressive type II EC, myometrial?invasion ? 50% of the uterine wall thickness, and distant metastases on both univariate and multivariate analysis. Moreover, the overexpression of SLUG and ZEB2 was shown to be significant predictors of adnexal involvement on univariate analysis. ZEB 2 overexpression was identified in multivariate analysis as another independent predictor associated with a lesser likelihood of type II EC. Both univariate and multivariate analyses demonstrated that SLUG expression was the only predictor of 5-year survival in the study group. The overexpression of SLUG was associated with a significant increase in mortality hazard on univariate analysis and was shown to be a highly significant predictor of death on multivariate analysis. Conclusions. Selected proteins of the EMT pathway play a role in endometrial carcinogenesis; SLUG and ZEB2 expressions in the primary tumor might predict clinical outcomes in EC and drive therapeutic decisions regarding adjuvant treatment in patients with this malignancy.
| S-EPMC7785369 | biostudies-literature
Project description:BackgroundThe frequent incidence of postsurgical recurrence issues in papillary thyroid cancer (PTC) patients is a primary concern considering the low cancer-related mortality. Previous studies have demonstrated that epithelial-mesenchymal transition (EMT) activation is closely related to PTC progression and invasion. In this study, we aimed to develop a novel EMT signature and ancillary nomogram to improve personalized prediction of progression-free interval (PFI).MethodsFirst, we carried out a differential analysis of PTC samples and pairwise normal thyroid samples to explore the differentially expressed genes (DEGs). The intersection of the DEGs with EMT-related genes (ERGs) were identified as differentially expressed EMT-related genes (DE-ERGs). We determined PFI-related DE-ERGs by Cox regression analysis and then established a novel gene classifier by LASSO regression analysis. We validated the signature in external datasets and in multiple cell lines. Further, we used uni- and multivariate analyses to identify independent prognostic characters.ResultsWe identified 244 prognosis-related DE-ERGs. The 244 DE-ERGs were associated with several pivotal oncogenic processes. We also constructed a novel 10-gene signature and relevant prognostic model for recurrence prediction of PTC. The 10-gene signature had a C-index of 0.723 and the relevant nomogram had a C-index of 0.776. The efficacy of the signature and nomogram was satisfying and closely correlated with relevant clinical parameters. Furthermore, the signature also had a unique potential in differentiating anaplastic thyroid cancer (ATC) samples.ConclusionsThe novel EMT signature and nomogram are useful and convenient for personalized management for thyroid cancer.
| S-EPMC9741981 | biostudies-literature
Project description:Snail family zinc finger 2 (SLUG) is related to epithelial-mesenchymal transition (EMT). Quaking (QKI) is an RNA binding protein and has been indicated to have a relationship with EMT by recent studies. The prognostic value of SLUG and QKI in breast cancer patients still needs exploration. We conducted Immunohistochemistry (IHC) to evaluate the protein expression of SLUG and QKI and the prognostic value in 108 breast cancer (BC) patients. The Bc-GenExMiner database was used to compare the mRNA levels of two genes in different subgroups of BC patients. Kaplan-Meier plotter were used for survival data of SLUG and QKI gene. We also mined the cBioPortal database for co-expression analysis of QKI and EMT markers. Our results suggested that patients with higher expression of SLUG and QKI showed shorter overall survival time. The mRNA level of SLUG and QKI were higher in ER negative, PR negative, ≤ 51 y, and TNBC patients. SLUG mRNA showed no survival significance, while higher QKI mRNA expression level was correlated with worse clinical outcome in Kaplan-Meier Plotter database. The cBioPortal database showed that QKI was correlated to SLUG as well as other EMT markers like TWIST2, VIM, and ZEB2. QKI was indicated to be a potential prognostic marker for BC patients, and combined expression of SLUG and QKI showed the best prognostic value. Co-expression analysis indicated that QKI was likely to have a correlation with SLUG and EMT.
| S-EPMC6949612 | biostudies-literature
Project description:Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays critical roles in malignant transformation and tumor progression. Previously, we have shown that microRNA-451 (miR-451) inhibits growth, increases chemo- or radiosensitivity and reverses epithelial to mesenchymal transition (EMT) in lung cancer. However, the roles of miR-451 in hepatocelluar carcinoma (HCC) progression and metastasis are still largely unknown. Reduced miR-451 in HCC tissues was observed to be significantly correlated with advanced clinical stage, metastasis and worse disease-free or overall survival. Through gain- and loss-of function experiments, we demonstrated that miR-451 inhibited cell growth, induced G0/G1 arrest and promoted apoptosis in HCC cells. Importantly, miR-451 could inhibit the migration and invasion in vitro, as well as in vivo metastasis of HCC cells through regulating EMT process. Moreover, the oncogene c-Myc was identified as a direct and functional target of miR-451 in HCC cells. Knockdown of c-Myc phenocopied the effects of miR-451 on EMT and metastasis of HCC cells, whereas overexpression of c-Myc partially attenuated the functions of miR-451 restoration. Furthermore, miR-451 downregulation-induced c-Myc overexpression leads to the activation of Erk1/2 signaling, which induces acquisition of EMT phenotype through regulation of GSK-3β/snail/E-cadherin and the increased expression of MMPs family members in HCC cells. Collectively, these data demonstrated that miR-451 is a novel prognostic biomarker for HCC patients and that function as a potential metastasis inhibitor in HCC cells through activation of the Erk1/2 signaling, at least partially by targeting c-Myc. Thus, targeting miR-451/c-Myc/Erk1/2 axis may be a potential strategy for the treatment of metastatic HCC.
| S-EPMC4621914 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) is critical in the development of coronary artery disease (CAD). However, landscapes of EMT-related genes have not been fully established in CAD. We identified the differentially expressed mRNAs and lncRNAs (DElncRNAs) from the Gene Expression Omnibus database. Pearson's correlation analysis, the least absolute shrinkage and selection operator regression, and support vector machine reverse feature elimination algorithms were used to screen EMT-related lncRNAs. The cis-trans regulatory networks were constructed based on EMT-related lncRNAs. Quantitative real-time polymerase chain reaction was performed to validate the expression of EMT-related genes in a cohort of six patients with CAD and six healthy controls. We further estimated the infiltration of the immune cells in CAD patients with five algorithms, and the correlation between EMT-related genes and infiltrating immune cells was analyzed. We identified eight EMT-related lncRNAs in CAD. The area under curve value was greater than 0.95. The immune analysis revealed significant CD8 T cells, monocytes, and NK cells in CAD and found that EMT-related lncRNAs were correlated with these immune cell subsets. Moreover, SNAI2, an EMT-TF gene, was found in the trans-regulatory network of EMT-related lncRNAs. Further, we found SNAI2 as a biomarker for the diagnosis of CAD but it also had a close correlation with immune cell subsets in CAD. Eight EMT-related lncRNAs and SNAI2 have important significance in the diagnosis of CAD patients.
| S-EPMC9034345 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) is a cellular process through which epithelial cells transform into mesenchymal cells. EMT-implicated genes initiate and promote cancer metastasis because mesenchymal cells have greater invasive and migration capacities than epithelial cells. In this pan-cancer analysis, we explored the relationship between gene expression changes and copy number variations (CNVs) for EMT-implicated genes. Based on curated 377 EMT-implicated genes from the literature, we identified 212 EMT-implicated genes associated with more frequent copy number gains (CNGs) than copy number losses (CNLs) using data from The Cancer Genome Atlas (TCGA). Then by correlating these CNV data with TCGA gene expression data, we identified 71 EMT-implicated genes with concordant CNGs and gene up-regulation in 20 or more tumor samples. Of those, 14 exhibited such concordance in over 110 tumor samples. These 14 genes were predominantly apoptosis regulators, which may implies that apoptosis is critical during EMT. Moreover, the 71 genes with concordant CNG and up-regulation were largely involved in cellular functions such as phosphorylation cascade signaling. This is the first observation of concordance between CNG and up-regulation of specific genes in hundreds of samples, which may indicate that somatic CNGs activate gene expression by increasing the gene dosage.
| S-EPMC5029734 | biostudies-literature
Project description:BackgroundGliomas are the most prevalent type of intracranial tumors. NKCC1 is an important regulator in tumor cell volume. We noticed that abnormally high NKCC1 expression resulted in changes in the shape and adhesion of glioma cells. However, little is known about the role of NKCC1 in the epithelial-mesenchymal transition (EMT) of gliomas. This study aims to clarify the biological function of NKCC1 in glioblastoma multiforme (GBM) progression.MethodsUsing data from The Cancer Genome Atlas (TCGA), we performed a Kaplan-Meier analysis on NKCC1 expression levels to estimate the rate of survival of mesenchymal GBM patients. The correlation between NKCC1 and EMT-related proteins was analyzed from the Gene Expression Profiling Interactive Analysis (GEPIA) server. We conducted Gene Set Enrichment Analysis (GSEA) to verify molecular signatures and pathways. We then studied the expression of NKCC1 in grade I-IV glioma tissue samples collected from patients using immunohistochemistry (IHC). Finally, we evaluated the effects of NKCC1 migration and invasion on the cellular behaviors of U251 cells using the transwell assay and western blots.ResultsHigh NKCC1 expression was associated with poor prognoses in mesenchymal GBM. Our results suggest a correlation between NKCC1 and EMT-protein markers: CDH2 and VIM. GSEA showed that gliomas, TGF-beta signaling and EMT were enriched in the NKCC1 high expression phenotype. Higher expression levels of NKCC1 in gliomas correlate with higher glioma grades. Transwell assay and western blot results demonstrated that the knockdown of NKCC1 led to a reduction in migration and invasion, while also inhibiting MMP-2 and MMP-9 expression in U251.ConclusionThese results suggest that high expression of NKCC1 regulates EMT in gliomas, providing a new therapeutic strategy for addressing the spread of gliomas by inhibiting the spread of intracranial tumors.
| S-EPMC7081783 | biostudies-literature