title: microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition.
abstract: Ovarian cancer is a leading cause of cancer deaths among women. Effective targets to treat advanced epithelial ovarian cancer (EOC) and biomarkers to predict treatment response are still lacking because of the complexity of pathways involved in ovarian cancer progression. Here we show that miR-181a promotes TGF-β-mediated epithelial-to-mesenchymal transition via repression of its functional target, Smad7. miR-181a and phosphorylated Smad2 are enriched in recurrent compared with matched-primary ovarian tumours and their expression is associated with shorter time to recurrence and poor outcome in patients with EOC. Furthermore, ectopic expression of miR-181a results in increased cellular survival, migration, invasion, drug resistance and in vivo tumour burden and dissemination. In contrast, miR-181a inhibition via decoy vector suppression and Smad7 re-expression results in significant reversion of these phenotypes. Combined, our findings highlight an unappreciated role for miR-181a, Smad7, and the TGF-β signalling pathway in high-grade serous ovarian cancer.
authors.affiliation: 1] Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA [2] Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA [3].
authors.forename: Aditya
authors.initials: A
authors.lastname: Parikh
authors.affiliation: 1] Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA [2] Case Comprehensive Cancer Center, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA [3].
authors.forename: Christine
authors.initials: C
authors.lastname: Lee
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA.
authors.forename: Peronne
authors.initials: P
authors.lastname: Joseph
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', via La Masa 19, 20156 Milano, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Marchini
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Baccarini
authors.affiliation: Department of Obstetrics and Gynecology, The Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Valentin
authors.initials: V
authors.lastname: Kolev
authors.affiliation: Department of Biology, Universtia' degli studi di Padova, Via U.Bassi 58/B, Padova 35121, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Romualdi
authors.affiliation: 1] Clinic of Obstetrics and Gynecology, University of Milano-Bicocca, San Gerardo Hospital, 20900 Monza, Italy [2] MaNGO Group, 20156 Milano, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Fruscio
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Hardik
authors.initials: H
authors.lastname: Shah
authors.affiliation: Department of Obstetrics and Gynecology, The Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Gavriel
authors.initials: G
authors.lastname: Mullokandov
authors.affiliation: Department of Obstetrics and Gynecology, The Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fishman
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', via La Masa 19, 20156 Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Department of Obstetrics and Gynecology, The Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Jamal
authors.initials: J
authors.lastname: Rahaman
authors.affiliation: 1] MaNGO Group, 20156 Milano, Italy [2] Department of Pathology, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Kalir
authors.affiliation: Department of Pathology, University Hospitals Case Medical Center, 2103 Cornell Road, Cleveland, Ohio 44106, USA.
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Redline
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Brown
authors.affiliation: 1] Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA [2] Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA [3] Case Comprehensive Cancer Center, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA [4] Institute for Transformative Molecular Medicine, Department of Medicine Case Western Q3 Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA.
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.affiliation: 1] Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA [2] Case Comprehensive Cancer Center, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA.
authors.forename: Analisa
authors.initials: A
authors.lastname: DiFeo
mesh_terms: D000328:Adult; D000368:Aged; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077216:Carcinoma, Ovarian Epithelial; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009367:Neoplasm Staging; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051899:Smad2 Protein / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1