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.

A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis / Vecchione, Andrea; B., Belletti; F., Lovat; S., Volinia; G., Chiappetta; Giglio, Simona; M., Sonego; Cirombella, Roberto; E. c., Onesti; Pellegrini, Patrizia; D., Califano; S., Pignata; S., Losito; R., Sorio; H., Alder; D., Wernicke; Stoppacciaro, Antonella; G., Baldassarre; C. m., Croce; Canzonieri, Vincenzo. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 110:24(2013), pp. 9845-9850. [10.1073/pnas.1305472110]

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

VECCHIONE, ANDREA;GIGLIO, SIMONA;CIROMBELLA, Roberto;PELLEGRINI, Patrizia;STOPPACCIARO, ANTONELLA;CANZONIERI, Vincenzo
2013

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.
Antineoplastic Agents; Blotting, Western; Carboplatin; Cell Line, Tumor; Coculture Techniques; Cystadenocarcinoma, Serous; Drug Resistance, Neoplasm; Female; Human Umbilical Vein Endothelial Cells; Humans; MicroRNAs; Neoplasms, Glandular and Epithelial; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms; Paclitaxel; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factor Receptor-2; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Multidisciplinary
01 Pubblicazione su rivista::01a Articolo in rivista
A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis / Vecchione, Andrea; B., Belletti; F., Lovat; S., Volinia; G., Chiappetta; Giglio, Simona; M., Sonego; Cirombella, Roberto; E. c., Onesti; Pellegrini, Patrizia; D., Califano; S., Pignata; S., Losito; R., Sorio; H., Alder; D., Wernicke; Stoppacciaro, Antonella; G., Baldassarre; C. m., Croce; Canzonieri, Vincenzo. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 110:24(2013), pp. 9845-9850. [10.1073/pnas.1305472110]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/523643
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