title: A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis.
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.
authors.affiliation: Division of Pathology and Medical Oncology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University Sapienza, Santo Andrea Hospital, 00100 Rome, Italy. Andrea.Vecchione@osumc.edu
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Gennaro
authors.initials: G
authors.lastname: Chiappetta
authors.forename: Simona
authors.initials: S
authors.lastname: Giglio
authors.forename: Maura
authors.initials: M
authors.lastname: Sonego
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirombella
authors.forename: Elisa Concetta
authors.initials: EC
authors.lastname: Onesti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pellegrini
authors.forename: Daniela
authors.initials: D
authors.lastname: Califano
authors.forename: Sandro
authors.initials: S
authors.lastname: Pignata
authors.forename: Simona
authors.initials: S
authors.lastname: Losito
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Canzonieri
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorio
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Dorothee
authors.initials: D
authors.lastname: Wernicke
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000098:blood supply / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C553315:MIRN217 microRNA, human; C572386:MIRN484 microRNA, human; C571933:MIRN642 microRNA, human; D035683:MicroRNAs; C467485:VEGFB protein, human; D042561:Vascular Endothelial Growth Factor B; D016190:Carboplatin; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel