title: miR-126&126* restored expressions play a tumor suppressor role by directly regulating ADAM9 and MMP7 in melanoma.
abstract: The abnormal expression of several microRNAs has a causal role in tumorigenesis with either antineoplastic or oncogenic functions. Here we demonstrated that miR-126 and miR-126* play a tumor suppressor role in human melanoma through the direct or indirect repression of several key oncogenic molecules. The expression levels of miR-126&126* were elevated in normal melanocytes and primary melanoma cell lines, whereas they markedly declined in metastatic cells. Indeed, the restored expression of miR-126&126* in two advanced melanoma cell lines was accompanied by a significant reduction of proliferation, invasion and chemotaxis in vitro as well as of growth and dissemination in vivo. In accordance, the reverse functional effects were obtained by knocking down miR-126&126* by transfecting antisense LNA oligonucleotides in melanoma cells. Looking for the effectors of these antineoplastic functions, we identified ADAM9 and MMP7, two metalloproteases playing a pivotal role in melanoma progression, as direct targets of miR-126&126*. In addition, as ADAM9 and MMP7 share a role in the proteolytic cleavage of the HB-EGF precursor, we looked for the effectiveness of this regulatory pathway in melanoma, confirming the decrease of HB-EGF activation as a consequence of miR-126&126*-dependent downmodulation of ADAM9 and MMP7. Finally, gene profile analyses showed that miR-126&126* reexpression was sufficient to inactivate other key signaling pathways involved in the oncogenic transformation, as PI3K/AKT and MAPK, and to restore melanogenesis, as indicated by KIT/MITF/TYR induction. In view of this miR-126&126* wide-ranging action, we believe that the replacement of these microRNAs might be considered a promising therapeutic approach.
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy.
authors: Nadia
authors: N
authors: Felli
authors: Federica
authors: F
authors: Felicetti
authors: Anna Maria
authors: AM
authors: Lustri
authors: M Cristina
authors: MC
authors: Errico
authors: Lisabianca
authors: L
authors: Bottero
authors: Alessio
authors: A
authors: Cannistraci
authors: Alessandra
authors: A
authors: De Feo
authors: Marina
authors: M
authors: Petrini
authors: Francesca
authors: F
authors: Pedini
authors: Mauro
authors: M
authors: Biffoni
authors: Ester
authors: E
authors: Alvino
authors: Massimo
authors: M
authors: Negrini
authors: Manuela
authors: M
authors: Ferracin
authors: Gianfranco
authors: G
authors: Mattia
authors: Alessandra
authors: A
authors: Carè
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D045744:Cell Line, Tumor; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000235:genetics* / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C527111:MIRN126 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D053495:Osteopontin; D051722:ADAM Proteins; C098339:ADAM9 protein, human; D020783:Matrix Metalloproteinase 7