Dataset Information

MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer.

ABSTRACT: BACKGROUND:Primary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy. Platinum resistant cancers progress/recur in approximately 25% of cases within six months. We aimed to identify clinically useful biomarkers of platinum resistance. METHODS:A database of ovarian cancer transcriptomic datasets including treatment and response information was set up by mining the GEO and TCGA repositories. Receiver operator characteristics (ROC) analysis was performed in R for each gene and these were then ranked using their achieved area under the curve (AUC) values. The most significant candidates were selected and in vitro functionally evaluated in four epithelial ovarian cancer cell lines (SKOV-3-, CAOV-3, ES-2 and OVCAR-3), using gene silencing combined with drug treatment in viability and apoptosis assays. We collected 94 tumor samples and the strongest candidate was validated by IHC and qRT-PCR in these. RESULTS:All together 1,452 eligible patients were identified. Based on the ROC analysis the eight most significant genes were JRK, CNOT8, RTF1, CCT3, NFAT2CIP, MEK1, FUBP1 and CSDE1. Silencing of MEK1, CSDE1, CNOT8 and RTF1, and pharmacological inhibition of MEK1 caused significant sensitization in the cell lines. Of the eight genes, JRK (p?=?3.2E-05), MEK1 (p?=?0.0078), FUBP1 (p?=?0.014) and CNOT8 (p?=?0.00022) also correlated to progression free survival. The correlation between the best biomarker candidate MEK1 and survival was validated in two independent cohorts by qRT-PCR (n?=?34, HR?=?5.8, p?=?0.003) and IHC (n?=?59, HR?=?4.3, p?=?0.033). CONCLUSION:We identified MEK1 as a promising prognostic biomarker candidate correlated to response to platinum based chemotherapy in ovarian cancer.

SUBMITTER: Penzvalto Z

PROVIDER: S-EPMC4247127 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer.

Pénzváltó Zsófia Z Lánczky András A Lénárt Julianna J Meggyesházi Nóra N Krenács Tibor T Szoboszlai Norbert N Denkert Carsten C Pete Imre I Győrffy Balázs B

BMC cancer 20141118

<h4>Background</h4>Primary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy. Platinum resistant cancers progress/recur in approximately 25% of cases within six months. We aimed to identify clinically useful biomarkers of platinum resistance.<h4>Methods</h4>A database of ovarian cancer transcriptomic datasets including treatment and response information was set up by mining the GEO and TCGA repositories. Receiver operator characteristics (ROC) analysis was ...[more]

PMID: 25408231

Similar Datasets

Project description:PurposeTo analyze the role of six human epididymis protein 4 (HE4)-related mitochondrial ribosomal proteins (MRPs) in ovarian cancer and selected MRPL15, which is most closely related to the tumorigenesis and prognosis of ovarian cancer, for further analyses.MethodsUsing STRING database and MCODE plugin in Cytoscape, six MRPs were identified among genes that are upregulated in response to HE4 overexpression in epithelial ovarian cancer cells. The Cancer Genome Atlas (TCGA) ovarian cancer, GTEX, Oncomine, and TISIDB were used to analyze the expression of the six MRPs. The prognostic impact and genetic variation of these six MRPs in ovarian cancer were evaluated using Kaplan-Meier Plotter and cBioPortal, respectively. MRPL15 was selected for immunohistochemistry and GEO verification. TCGA ovarian cancer data, gene set enrichment analysis, and Enrichr were used to explore the mechanism of MRPL15 in ovarian cancer. Finally, the relationship between MRPL15 expression and immune subtype, tumor-infiltrating lymphocytes, and immune regulatory factors was analyzed using TCGA ovarian cancer data and TISIDB.ResultsSix MRPs (MRPL10, MRPL15, MRPL36, MRPL39, MRPS16, and MRPS31) related to HE4 in ovarian cancer were selected. MRPL15 was highly expressed and amplified in ovarian cancer and was related to the poor prognosis of patients. Mechanism analysis indicated that MRPL15 plays a role in ovarian cancer through pathways such as the cell cycle, DNA repair, and mTOR 1 signaling. High expression of MRPL15 in ovarian cancer may be associated with its amplification and hypomethylation. Additionally, MRPL15 showed the lowest expression in C3 ovarian cancer and was correlated with proliferation of CD8+ T cells and dendritic cells as well as TGFβR1 and IDO1 expression.ConclusionMRPL15 may be a prognostic indicator and therapeutic target for ovarian cancer. Because of its close correlation with HE4, this study provides insights into the mechanism of HE4 in ovarian cancer.

Project description:Background: Drug resistance is a major obstacle to successful chemotherapy for epithelial ovarian cancer (EOC). We found a subset of miRNAs associated with the response to first-line platinum-based chemotherapy in EOC by microarray, and miR-206 was one of the most significant miRNAs. The purposes of this study were to evaluate the prognostic and platinum-resistance predictive value of miR-206 in EOC patients and to investigate the functional roles of miR-206 in regulating the platinum resistance of EOC and the underlying mechanism.Methods: MiRNA expression profiling in EOC specimens was performed using a TaqMan miRNA array. miR-206 expression was confirmed by quantitative real-time PCR (qRT-PCR) analysis. Overexpression of miR-206 in EOC cell lines was achieved by the stable transfection of a recombinant plasmid. In vitro assays of cisplatin cytotoxicity, cell cycle distribution, apoptosis, transwell invasion and cell scratching were employed. Connexin 43 (Cx43) expression was detected by Western blotting. Murine xenograft models were used to determine the effects of miR-206 on platinum resistance in vivo.Results: miR-206 expression was increased in primary platinum-resistant EOC. High miR-206 expression was related to poor prognosis in EOC patients who received platinum-based chemotherapy and predicted chemoresistance to platinum treatment. Overexpression of miR-206 in cisplatin-sensitive EOC cell lines significantly increased cell viability, migration and invasion in the presence of cisplatin and decreased cisplatin-induced apoptosis. Cx43, a target gene of miR-206, was negatively regulated by miR-206 in EOC cell lines and significantly related to better prognosis in patients who received platinum-based chemotherapy (KmPlot). miR-206 had high expression and Cx43 had low expression in platinum-sensitive EOC cell lines compared with resistant ones. In vivo murine xenograft models showed that miR-206 profoundly promoted the chemoresistance of EOC to cisplatin treatment.Conclusion: miR-206 was highly expressed in primary platinum-resistant EOCs and functionally promoted platinum resistance in part by downregulating Cx43 expression, thereby providing a useful biomarker for prognostic and platinum-resistance prediction.

Project description:PurposeThe dysregulation of arrestin domain containing 3 (ARRDC3) has an important effect on oncogenesis and tumor progression in many cancers, including renal cell carcinoma and breast cancer. However, the role of ARRDC3 in ovarian cancer (OC) has not been reported.MethodsThe present study explored the diagnostic and prognostic roles of ARRDC3 in ovarian cancer using GEPIA, ONCOMINE, GEO, and Kaplan-Meier Plotter databases for training and validation. Then, we conducted a stratified analysis for clinicopathological factors using Kaplan-Meier Plotter and GEPIA databases. To further explore the mechanisms, we also used the MIST database to visualize the protein-protein interaction network of ARRDC3 associated with OC. The gene-gene interaction network was visualized by GeneMANIA plugin in Cytoscape 3.8.0 software, and the associated co-expression genes of ARRDC3 were analyzed by the cBioPortal database. The 100 top co-expression genes chosen for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used by the DAVID website.ResultsA significant difference in ARRDC3 mRNA expression was found between OC and normal ovary tissues. ARRDC3 could potentially be implicated in the diagnosis of OC. A high ARRDC3 mRNA expression level was associated with poor overall survival and progression-free survival. However, no significance was reported in respect to post progression survival. Except for histology, which had no prognostic value for PPS in stratified analysis, stratified analysis of other factors had prognostic value for OS, PFS, and PPS. Interestingly, we found a positive correlation between ARRDC3 expression and CD8+ T cells, macrophages, neutrophils, and dendritic cells, indicating that ARRDC3 might be associated with immune infiltration of these immune cells. Co-expression genes enrichment analysis found that they were involved in the Renin-angiotensin system pathway.ConclusionDifferentially expressed ARRDC3 might be a potential prognostic and diagnostic marker in Ovarian Cancer.

Dataset Information

MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer.

Publications

MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets