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; Analisa DiFeo

doi:10.1038/ncomms3977

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

Nat Commun. 2014:5:2977. doi: 10.1038/ncomms3977.

Authors

Aditya Parikh¹, Christine Lee², Peronne Joseph³, Sergio Marchini⁴, Alessia Baccarini⁵, Valentin Kolev⁶, Chiara Romualdi⁷, Robert Fruscio⁸, Hardik Shah⁵, Feng Wang⁶, Gavriel Mullokandov⁵, David Fishman⁶, Maurizio D'Incalci⁴, Jamal Rahaman⁶, Tamara Kalir⁹, Raymond W Redline¹⁰, Brian D Brown⁵, Goutham Narla¹¹, Analisa DiFeo¹²

Affiliations

¹ 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].
² 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].
³ Case Comprehensive Cancer Center, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA.
⁴ Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', via La Masa 19, 20156 Milano, Italy.
⁵ Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
⁶ Department of Obstetrics and Gynecology, The Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
⁷ Department of Biology, Universtia' degli studi di Padova, Via U.Bassi 58/B, Padova 35121, Italy.
⁸ 1] Clinic of Obstetrics and Gynecology, University of Milano-Bicocca, San Gerardo Hospital, 20900 Monza, Italy [2] MaNGO Group, 20156 Milano, Italy.
⁹ 1] MaNGO Group, 20156 Milano, Italy [2] Department of Pathology, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
¹⁰ Department of Pathology, University Hospitals Case Medical Center, 2103 Cornell Road, Cleveland, Ohio 44106, USA.
¹¹ 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.
¹² 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Carcinoma, Endometrioid / genetics*
Carcinoma, Endometrioid / metabolism
Carcinoma, Endometrioid / pathology
Carcinoma, Ovarian Epithelial
Cell Movement / genetics
Cell Survival / genetics
Disease Progression
Drug Resistance, Neoplasm / genetics
Epithelial-Mesenchymal Transition / genetics*
Female
Gene Expression Regulation, Neoplastic*
Humans
MicroRNAs / genetics*
Middle Aged
Neoplasm Invasiveness / genetics
Neoplasm Staging
Neoplasms, Cystic, Mucinous, and Serous / genetics*
Neoplasms, Cystic, Mucinous, and Serous / metabolism
Neoplasms, Cystic, Mucinous, and Serous / pathology
Neoplasms, Glandular and Epithelial / genetics*
Neoplasms, Glandular and Epithelial / metabolism
Neoplasms, Glandular and Epithelial / pathology
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Phosphorylation
Smad2 Protein / metabolism*
Smad7 Protein / metabolism*
Transforming Growth Factor beta1 / metabolism*

Substances

MIrn181 microRNA, human
MicroRNAs
SMAD2 protein, human
SMAD7 protein, human
Smad2 Protein
Smad7 Protein
TGFB1 protein, human
Transforming Growth Factor beta1

Abstract

Publication types

MeSH terms

Substances

Grants and funding