title: miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma.
abstract: Thyroid cancer incidence is rapidly increasing. Papillary Thyroid Carcinoma (PTC), the most frequent hystotype, usually displays good prognosis, but no effective therapeutic options are available for the fraction of progressive PTC patients. BRAF and RET/PTC are the most frequent driving genetic lesions identified in PTC. We developed two complementary in vitro models based on RET/PTC1 oncogene, starting from the hypothesis that miRNAs modulated by a driving PTC-oncogene are likely to have a role in thyroid neoplastic processes. Through this strategy, we identified a panel of deregulated miRNAs. Among these we focused on miR-199a-3p and showed its under-expression in PTC specimens and cell lines. We demonstrated that miR-199a-3p restoration in PTC cells reduces MET and mTOR protein levels, impairs migration and proliferation and, more interesting, induces lethality through an unusual form of cell death similar to methuosis, caused by macropinocytosis dysregulation. Silencing MET or mTOR, both involved in survival pathways, does not recapitulate miR-199a-3p-induced cell lethality, thus suggesting that the cooperative regulation of multiple gene targets is necessary. Integrated analysis of miR-199a-3p targets unveils interesting networks including HGF and macropinocytosis pathways. Overall our results indicate miR-199a-3p as a tumor suppressor miRNA in PTC.
authors.affiliation: Molecular Mechanisms Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Minna
authors.forename: Paola
authors.initials: P
authors.lastname: Romeo
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.forename: Matteo
authors.initials: M
authors.lastname: Dugo
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cassinelli
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.forename: Debora
authors.initials: D
authors.lastname: Degl'Innocenti
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casalini
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Angela
authors.initials: A
authors.lastname: Greco
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Borrello
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D035683:MicroRNAs / Q000235:genetics*; D010873:Pinocytosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; C531408:mirn199 microRNA, human; C546842:MTOR protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases