title: RNA interference inhibition of matrix metalloproteinase-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis.
abstract: Melanoma incidence is increasing worldwide, and metastatic melanoma is almost completely resistant to every known therapy. New approaches to treating melanoma are urgently needed, and a greater understanding of the biology of melanoma invasion and metastasis will aid in their creation. A high proportion of invasive melanomas have a constitutively active Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascade; however, the downstream effectors of ERK signaling that contribute to melanoma invasion and metastasis are unknown. ERK signaling drives the production of the interstitial collagenase matrix metalloproteinase-1 (MMP-1), which is expressed specifically by invasive melanomas. Using short hairpin RNAs (shRNA) to knock down MMP-1 expression in a human melanoma cell line, we investigated the role of MMP-1 in melanoma metastasis in a xenograft model. Knockdown of MMP-1 had no effect on primary tumor growth, but reduction of MMP-1 expression significantly decreased the ability of the melanoma to metastasize from the orthotopic site in the dermis to the lung. Mechanistically, tumor cells expressing MMP-1 shRNAs had diminished collagenase activity, which is required for tumor cell invasion. Additionally, attenuation of MMP-1 expression reduced angiogenesis. These results show, for the first time, that targeted inhibition of MMP-1, a single effector of the Raf/MEK/ERK signaling cascade, prevents the progression of melanoma from a primary to metastatic tumor and, as such, may represent a useful therapeutic tool in controlling this disease.
authors.affiliation: Department of Biochemistry, Norris Cotton Cancer Center, Lebanon, New Hampshire, USA.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Blackburn
authors.forename: C Harker
authors.initials: CH
authors.lastname: Rhodes
authors.forename: Charles I
authors.initials: CI
authors.lastname: Coon
authors.forename: Constance E
authors.initials: CE
authors.lastname: Brinckerhoff
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017364:Collagenases / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D017364:Collagenases; D020781:Matrix Metalloproteinase 1