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Cross?validation of genes potentially associated with neoadjuvant chemotherapy and platinum?based chemoresistance in epithelial ovarian carcinoma.

ABSTRACT: Ovarian carcinomas have the poorest prognosis and the highest mortality among gynecological malignancies. Neoadjuvant chemotherapy (NACT) is considered as a novel therapeutic strategy and an alternative treatment for advanced epithelial ovarian cancer (AEOC). The aim of the present study was to identify the core genes related to platinum?based NACT resistance in AEOC and to allow screening at the molecular level for the most appropriate ovarian cancer patients for NACT. We obtained three drug?resistant microarrays GSE114206, GSE41499 and GSE33482 from the Gene Expression Omnibus (GEO) database as well as a microarray representing NACT, GSE109934. Bioinformatics analysis revealed the nature of the four potential candidate genes for using in functional enrichment analyses and interaction network construction. The potential associations and possible genetic alterations among the DEGs were summarized using the STRING database in Cytoscape and the cBioPortal visualization tool, respectively. A total of 63 genes were identified as DEGs from GSE109934 representing NACT. From the drug?resistant GSE114206 and GSE41499 datasets, 106 DEGs containing 36 upregulated genes and 70 downregulated genes were selected, and from the drug?resistant GSE114206 and GSE33482 datasets, 406 DEGs with 157 upregulated genes and 249 downregulated genes were selected. The 36 upregulated DEGs and the 70 downregulated genes were notably abundant in the different categories. In KEGG pathway analysis, the 157 upregulated genes and the 249 downregulated genes were concentrated in distinctive signaling pathways. Four potential genes associated with NACT and platinum?based chemoresistance were screened, including nuclear factor of activated T?cells, cytoplasmic 1 (NAFTc1), Kruppel?like factor 4 (KLF4), nuclear receptor subfamily 4 group A member 3 (NR4A3) and hepatocyte growth factor (HGF). Our study showed that the mRNA expression levels of NAFTc1, NR4A3 and HGF were increased in drug?resistant OC cell lines (all P<0.01), whereas the mRNA expression levels of KLF4 were notably lower in the SKOV3?CDDP and HeyA8?CDDP cell line (all P<0.01) but higher in the A2780?CBP cell line. The NAFTc1, KLF4, NR4A3 and HGF genes may be potential therapeutic targets for NACT and platinum?based chemoresistance factors as well as candidate biomarkers in AEOC. Determination of the expression levels of these four genes in tumor tissues before planning NACT treatment or initial surgery would be beneficial for AEOC patients.

SUBMITTER: Zhang K

PROVIDER: S-EPMC7388274 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cross‑validation of genes potentially associated with neoadjuvant chemotherapy and platinum‑based chemoresistance in epithelial ovarian carcinoma.

Zhang Kai K Wang Weihan W Chen Lingli L Liu Yulin Y Hu Jiali J Guo Fei F Tian Wenyan W Wang Yingmei Y Xue Fengxia F

Oncology reports 20200702 3

Ovarian carcinomas have the poorest prognosis and the highest mortality among gynecological malignancies. Neoadjuvant chemotherapy (NACT) is considered as a novel therapeutic strategy and an alternative treatment for advanced epithelial ovarian cancer (AEOC). The aim of the present study was to identify the core genes related to platinum‑based NACT resistance in AEOC and to allow screening at the molecular level for the most appropriate ovarian cancer patients for NACT. We obtained three drug‑re ...[more]

PMID: 32705213

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Project description:BACKGROUND:The 5-year cancer specific survival (CSS) for patients with muscle invasive urothelial carcinoma of the bladder (MIBC) treated with cystectomy alone is approximately 50%. Platinum based neoadjuvant chemotherapy (NAC) plus cystectomy results in a marginal 5-10% increase in 5-year CSS in MIBC. Interestingly, responders to NAC (<ypT2) have a 5-year CSS of 90% which is in stark contrast to the 30-40% CSS for those whose MIBC is resistance to NAC. While the implementation of NAC for MIBC is increasing, it is still not widely utilized due to concerns related to delay of cystectomy, potential side-effects, and inability to predict effectiveness. Recently suggested molecular signatures of chemoresponsiveness, which could prove useful in this setting, would be of considerable utility but are yet to be translated into clinical practice. METHODS:mRNA expression data from a prior report on a NAC-treated MIBC cohort were re-analyzed in conjunction with the antibody database of the Human Protein Atlas (HPA) to identify candidate protein based biomarkers detectable by immunohistochemistry (IHC). These candidate biomarkers were subsequently tested in tissue microarrays derived from an independent cohort of NAC naive MIBC biopsy specimens from whom the patients were treated with neoadjuvant gemcitabine cisplatin NAC and subsequent cystectomy. The clinical parameters that have been previously associated with NAC response were also examined in our cohort. RESULTS:Our analyses of the available mRNA gene expression data in a discovery cohort (n = 33) and the HPA resulted in 8 candidate protein biomarkers. The combination of GDPD3 and SPRED1 resulted in a multivariate classification tree that was significantly associated with NAC response status (Goodman-Kruskal ? = 0.85 p<0.0001) in our independent NAC treated MIBC cohort. This model was independent of the clinical factors of age and clinical tumor stage, which have been previously associated with NAC response by our group. The combination of both these protein biomarkers detected by IHC in biopsy specimens along with the relevant clinical parameters resulted in a prediction model able to significantly stratify the likelihood of NAC resistance in our cohort (n = 37) into two well separated halves: low-26% n = 19 and high-89% n = 18, Fisher's exact p = 0.0002). CONCLUSION:We illustrate the feasibility of translating a gene expression signature of NAC response from a discovery cohort into immunohistochemical markers readily applicable to MIBC biopsy specimens in our independent cohort. The results from this study are being characterized in additional validation cohorts. Additionally, we anticipate that emerging somatic mutations in MIBC will also be important for NAC response prediction. The relationship of the findings in this study to the current understanding of variant histologic subtypes of MIBC along with the evolving molecular subtypes of MIBC as it relates to NAC response remains to be fully characterized.

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.

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Cross?validation of genes potentially associated with neoadjuvant chemotherapy and platinum?based chemoresistance in epithelial ovarian carcinoma.

Publications

Cross‑validation of genes potentially associated with neoadjuvant chemotherapy and platinum‑based chemoresistance in epithelial ovarian carcinoma.

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