TY - JOUR
T1 - A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis
AU - Vecchione, Andrea
AU - Belletti, Barbara
AU - Lovat, Francesca
AU - Volinia, Stefano
AU - Chiappetta, Gennaro
AU - Giglio, Simona
AU - Sonego, Maura
AU - Cirombella, Roberto
AU - Onesti, Elisa Concetta
AU - Pellegrini, Patrizia
AU - Califano, Daniela
AU - Pignata, Sandro
AU - Losito, Simona
AU - Canzonieri, Vincenzo
AU - Sorio, Roberto
AU - Alder, Hansjuerg
AU - Wernicke, Dorothee
AU - Stoppacciaro, Antonella
AU - Baldassarre, Gustavo
AU - Croce, Carlo M.
PY - 2013/6/11
Y1 - 2013/6/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878986540&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878986540&partnerID=8YFLogxK
U2 - 10.1073/pnas.1305472110
DO - 10.1073/pnas.1305472110
M3 - Article
C2 - 23697367
AN - SCOPUS:84878986540
VL - 110
SP - 9845
EP - 9850
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 24
ER -