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Altered expression pattern of topoisomerase IIalpha in ovarian tumor epithelial and stromal cells after platinum-based chemotherapy.

ABSTRACT: OBJECTIVE: The aim of this study was to evaluate the expression of topoisomerase IIalpha (TOP2A) in epithelial and stromal cells of ovarian cancer. METHODS: TOP2A expression was analyzed prospectively in normal and tumor epithelial and adjacent stromal cells using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) after laser microdissection (n = 38), RNA in situ hybridization (n = 13), and immunohistochemistry (n = 69). RESULTS: TOP2A mRNA was detected by RNA in situ hybridization in all ovarian cancer samples, with stronger hybridization signals in tumor epithelial cells compared to adjacent stromal cells. The same expression pattern was found by immunohistochemistry (P = .0001). Very interestingly, specific change was found in recurrent ovarian cancer after platinum-based chemotherapy: TOP2A expression decreased in tumor epithelial cells of recurrent ovarian cancer compared to primary ovarian cancer (P = .056), whereas it increased in tumor-adjacent stromal cells in carboplatin-treated recurrent tumors compared to primary ovarian cancer (P = .023). CONCLUSION: TOP2A mRNA and protein expression in ovarian cancer exhibits specific patterns in tumor epithelial and adjacent stromal cells, which are differentially modulated after platinum-based chemotherapy. These data support the recently discovered importance of the stromal compartment in tumor progression and suggest that tumor stromal cells might be relevant to the development of chemotherapy resistance in ovarian cancer.

SUBMITTER: Chekerov R

PROVIDER: S-EPMC1584288 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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Altered expression pattern of topoisomerase IIalpha in ovarian tumor epithelial and stromal cells after platinum-based chemotherapy.

Chekerov Radoslav R Klaman Irina I Zafrakas Menelaos M Könsgen Dominique D Mustea Alexander A Petschke Beate B Lichtenegger Werner W Sehouli Jalid J Dahl Edgar E

Neoplasia (New York, N.Y.) 20060101 1

<h4>Objective</h4>The aim of this study was to evaluate the expression of topoisomerase IIalpha (TOP2A) in epithelial and stromal cells of ovarian cancer.<h4>Methods</h4>TOP2A expression was analyzed prospectively in normal and tumor epithelial and adjacent stromal cells using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) after laser microdissection (n = 38), RNA in situ hybridization (n = 13), and immunohistochemistry (n = 69).<h4>Results</h4>TOP2A mRNA was det ...[more]

PMID: 16533424

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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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Altered expression pattern of topoisomerase IIalpha in ovarian tumor epithelial and stromal cells after platinum-based chemotherapy.

Publications

Altered expression pattern of topoisomerase IIalpha in ovarian tumor epithelial and stromal cells after platinum-based chemotherapy.

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