miR-451a is underexpressed and targets AKT/mTOR pathway in papillary thyroid carcinoma

// Emanuela Minna 1 , Paola Romeo 1 , Matteo Dugo 2 , Loris De Cecco 2 , Katia Todoerti 3 , Silvana Pilotti 4 , Federica Perrone 4 , Ettore Seregni 5 , Luca Agnelli 6 , Antonino Neri 6, 7 , Angela Greco 1 , Maria Grazia Borrello 1 1 Department of Experimental Oncology and Molecular Medicine, Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Department of Experimental Oncology and Molecular Medicine, Functional Genomics Core Facility, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 3 Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy 4 Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 5 Department of Diagnostic Imaging and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 6 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy 7 Hematology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy Correspondence to: Maria Grazia Borrello, e-mail: mariagrazia.borrello@istitutotumori.mi.it Keywords: papillary thyroid carcinoma, miR-451a, miRNA, RET/PTC, AKT pathway Received: December 18, 2015      Accepted: January 26, 2016      Published: February 8, 2016 ABSTRACT Papillary Thyroid Carcinoma (PTC) is the most frequent thyroid cancer. Although several PTC-specific miRNA profiles have been reported, only few upregulated miRNAs are broadly recognized, while less consistent data are available about downregulated miRNAs. In this study we investigated miRNA deregulation in PTC by miRNA microarray, analysis of a public dataset from The Cancer Genome Atlas (TCGA), literature review and meta-analysis based on a univocal miRNA identifier derived from miRBase v21. A list of 18 miRNAs differentially expressed between PTC and normal thyroid was identified and validated in the TCGA dataset. Furthermore, we compared our signature with miRNA profiles derived from 15 studies selected from literature. Then, to select possibly functionally relevant miRNA, we integrated our miRNA signature with those from two in vitro cell models based on the PTC-driving oncogene RET/PTC1. Through this strategy, we identified commonly deregulated miRNAs, including miR-451a, which emerged also by our meta-analysis as the most frequently reported downregulated miRNA. We showed that lower expression of miR-451a correlates with aggressive clinical-pathological features of PTC as tall cell variant, advanced stage and extrathyroid extension. In addition, we demonstrated that ectopic expression of miR-451a impairs proliferation and migration of two PTC-derived cell lines, reduces the protein levels of its recognized targets MIF, c-MYC and AKT1 and attenuates AKT/mTOR pathway activation. Overall, our study provide both an updated overview of miRNA deregulation in PTC and the first functional evidence that miR-451a exerts tumor suppressor functions in this neoplasia.