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: Nadia Felli, Federica Felicetti, Anna Maria Lustri, M Cristina Errico, Lisabianca Bottero, Alessio Cannistraci, Alessandra De Feo, Marina Petrini, Francesca Pedini, Mauro Biffoni, Ester Alvino, Massimo Negrini, Manuela Ferracin, Gianfranco Mattia, Alessandra Carè
• Journal: PloS one (PLoS One) Vol. 8 Issue 2 Pg. e56824 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23437250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HBEGF protein, human
• Hbegf protein, mouse
• Heparin-binding EGF-like Growth Factor
• Intercellular Signaling Peptides and Proteins
• MIRN126 microRNA, human
• Membrane Proteins
• MicroRNAs
• Osteopontin
• ADAM Proteins
• ADAM9 protein, human
• Matrix Metalloproteinase 7

Topics

• ADAM Proteins (genetics, metabolism)
• Animals
• Base Pairing
• Base Sequence
• Cell Line, Tumor
• Disease Progression
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Heparin-binding EGF-like Growth Factor
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Matrix Metalloproteinase 7 (genetics, metabolism)
• Melanocytes (metabolism)
• Melanoma (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Mice
• MicroRNAs (genetics)
• Osteopontin (genetics, metabolism)
• Proteolysis
• RNA Interference
• Skin Neoplasms (genetics, metabolism)
• Xenograft Model Antitumor Assays