microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial–mesenchymal transition

Aditya Parikh, Christine Lee, Peronne Joseph, Sergio Marchini, Alessia Baccarini, Valentin Kolev, Chiara Romualdi, Robert Fruscio, Hardik Shah, Feng Wang, Gavriel Mullokandov, David Fishman, Maurizio D’Incalci, Jamal Rahaman, Tamara Kalir, Raymond W. Redline, Brian D. Brown, Goutham Narla and Analisa DiFeo ()
Additional contact information
Aditya Parikh: Mount Sinai School of Medicine
Christine Lee: Mount Sinai School of Medicine
Peronne Joseph: Case Comprehensive Cancer Center, Case Western Reserve University
Sergio Marchini: IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, via La Masa 19, 20156 Milano, Italy
Alessia Baccarini: Mount Sinai School of Medicine
Valentin Kolev: The Mount Sinai School of Medicine
Chiara Romualdi: Universtia' degli studi di Padova, Via U.Bassi 58/B
Robert Fruscio: Clinic of Obstetrics and Gynecology, University of Milano-Bicocca, San Gerardo Hospital
Hardik Shah: Mount Sinai School of Medicine
Feng Wang: The Mount Sinai School of Medicine
Gavriel Mullokandov: Mount Sinai School of Medicine
David Fishman: The Mount Sinai School of Medicine
Maurizio D’Incalci: IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, via La Masa 19, 20156 Milano, Italy
Jamal Rahaman: The Mount Sinai School of Medicine
Tamara Kalir: MaNGO Group
Raymond W. Redline: University Hospitals Case Medical Center
Brian D. Brown: Mount Sinai School of Medicine
Goutham Narla: Mount Sinai School of Medicine
Analisa DiFeo: Mount Sinai School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms3977

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