A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis

Andrea Vecchione, Barbara Belletti, Francesca Lovat, Stefano Volinia, Gennaro Chiappetta, Simona Giglio, Maura Sonego, Roberto Cirombella, Elisa Concetta Onesti, Patrizia Pellegrini, Daniela Califano, Sandro Pignata, Simona Losito, Vincenzo Canzonieri, Roberto Sorio, Hansjuerg Alder, Dorothee Wernicke, Antonella Stoppacciaro, Gustavo Baldassarre, Carlo M. Croce

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Abstract

Epithelial ovarian cancer is the most lethal gynecologic malignancy; it is highly aggressive and causes almost 125,000 deaths yearly. Despite advances in detection and cytotoxic therapies, a low percentage of patients with advanced stage disease survive 5 y after the initial diagnosis. The high mortality of this disease is mainly caused by resistance to the available therapies. Here, we profiled microRNA (miR) expression in serous epithelial ovarian carcinomas to assess the possibility of a miR signature associated with chemoresistance. We analyzed tumor samples from 198 patients (86 patients as a training set and 112 patients as a validation set) for human miRs. A signature of 23 miRs associated with chemoresistance was generated by array analysis in the training set. Quantitative RT-PCR in the validation set confirmed that three miRs (miR-484, -642, and -217) were able to predict chemoresistance of these tumors. Additional analysis of miR-484 revealed that the sensitive phenotype is caused by a modulation of tumor vasculature through the regulation of the VEGFB and VEGFR2 pathways. We present compelling evidence that three miRs can classify the response to chemotherapy of ovarian cancer patients in a large multicenter cohort and that one of these three miRs is involved in the control of tumor angiogenesis, indicating an option in the treatment of these patients. Our results suggest, in fact, that blockage of VEGF through the use of an anti-VEGFA antibody may not be sufficient to improve survival in ovarian cancer patients unless VEGFB signaling is also blocked.

Original languageEnglish
Pages (from-to)9845-9850
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number24
DOIs
Publication statusPublished - Jun 11 2013

ASJC Scopus subject areas

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    Vecchione, A., Belletti, B., Lovat, F., Volinia, S., Chiappetta, G., Giglio, S., Sonego, M., Cirombella, R., Onesti, E. C., Pellegrini, P., Califano, D., Pignata, S., Losito, S., Canzonieri, V., Sorio, R., Alder, H., Wernicke, D., Stoppacciaro, A., Baldassarre, G., & Croce, C. M. (2013). A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis. Proceedings of the National Academy of Sciences of the United States of America, 110(24), 9845-9850. https://doi.org/10.1073/pnas.1305472110