title: Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis.
abstract: Previous studies have demonstrated that high mobility group A proteins have a critical role on the onset of human pituitary adenomas. Indeed, both high mobility group A (HMGA) genes are overexpressed in pituitary adenomas, and consistently transgenic mice overexpressing either the Hmga1 or the Hmga2 gene develop mixed growth hormone/prolactin (GH-PRL)-secreting pituitary adenomas. Trisomy of chromosome 12, where HMGA2 is located, and/or amplification of the HMGA2 gene locus account for the HMGA2 overexpression in most human prolactinomas. Conversely, HMGA1 overexpression is not associated to any rearrangement or amplification of the HMGA1 locus. We have first identified micro RNAs (miRNAs) able to target both HMGA1 and HMGA2 messenger RNAs. Then, all of these miRNAs have been found downregulated in pituitary adenomas of different histotypes, compared with normal pituitary. Interestingly, their downregulation was also observed in nonfunctioning pituitary adenomas where HMGA2 overexpression is not associated to any alteration of the HMGA2 locus. Functional studies show that all these HMGA-targeting miRNAs inhibit the proliferation of the rat pituitary adenoma cell line GH3. Therefore, these results indicate that the downregulation of the miRNAs able to target the HMGA genes could contribute to increase HMGA protein levels in human pituitary adenomas, and then to pituitary tumorigenesis.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR Dipartimento di Biologia e Patologia Cellulare e Molecolare Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, Naples, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Palmieri
authors.forename: D
authors.initials: D
authors.lastname: D'Angelo
authors.forename: T
authors.initials: T
authors.lastname: Valentino
authors.forename: I
authors.initials: I
authors.lastname: De Martino
authors.forename: A
authors.initials: A
authors.lastname: Ferraro
authors.forename: A
authors.initials: A
authors.lastname: Wierinckx
authors.forename: M
authors.initials: M
authors.lastname: Fedele
authors.forename: J
authors.initials: J
authors.lastname: Trouillas
authors.forename: A
authors.initials: A
authors.lastname: Fusco
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024003:HMGA Proteins / Q000235:genetics* / Q000378:metabolism; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid
chemical_list: D020413:3' Untranslated Regions; D024003:HMGA Proteins; D025741:HMGA1a Protein; D025743:HMGA2 Protein; D035683:MicroRNAs; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; C542543:MIRN196 microRNA, human; C528163:MIRN26 microRNA, human; C487931:mirnlet7 microRNA, human