title: Constitutive activation of the ETS-1-miR-222 circuitry in metastatic melanoma.
abstract: MicroRNAs-221 and -222 are highly upregulated in several solid tumors, including melanomas. We demonstrate that the proto-oncogene ETS-1, involved in the pathogenesis of cancers of different origin, is a transcriptional regulator of miR-222 by direct binding to its promoter region. Differently from 293FT cells or early stage melanomas, where unphosphorylated ETS-1 represses miR-222 transcription, in metastatic melanoma the constitutively Thr-38 phosphorylated fraction of ETS-1 induces miR-222. Despite its stepwise decreased expression along with melanoma progression, the oncogenic activity of ETS-1 relies on its RAS/RAF/ERK-dependent phosphorylation status more than on its total amount. To close the loop, we demonstrate ETS-1 as a direct target of miR-222, but not miR-221, showing the novel option of their uncoupled functions. In addition, a spatial redistribution of ETS-1 protein from the nucleus to the cytoplasm is also evidenced in advanced melanoma cells. Finally, in vivo studies confirmed the contribution of miR-222 to the increased invasive potential obtained by ETS- silencing.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Mattia
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Errico
authors.forename: Federica
authors.initials: F
authors.lastname: Felicetti
authors.forename: Marina
authors.initials: M
authors.lastname: Petrini
authors.forename: Lisabianca
authors.initials: L
authors.lastname: Bottero
authors.forename: Luisa
authors.initials: L
authors.lastname: Tomasello
authors.forename: Paolo
authors.initials: P
authors.lastname: Romania
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boe
authors.forename: Patrizia
authors.initials: P
authors.lastname: Segnalini
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Virgilio
authors.forename: Mario P
authors.initials: MP
authors.lastname: Colombo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carè
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D035683:MicroRNAs; D010769:Phosphothreonine; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1; D013755:Tetradecanoylphorbol Acetate; C494041:ETS1 protein, human; C000715470:MAS1 protein, human; C525709:MIR221, human; C525710:MIR222, human