title: MDA-9/syntenin is essential for factor VIIa-induced signaling, migration, and metastasis in melanoma cells.
abstract: Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, is a novel gene that positively regulates cancer cell motility, invasion, and metastasis through distinct biochemical and signaling pathways, but how MDA-9/syntenin is regulated in response to signals with the extracellular environment and promotes tumor progression is unclear. We now demonstrate that MDA-9/syntenin is dramatically up-regulated by a combination of rFVIIa and factor F(X) in malignant melanoma. Induction of MDA-9/syntenin in melanoma was found to occur in a thrombin-independent signaling pathway and involves the PAR-1/c-Src/Rho GTPases Rac1 and Cdc42/c-Jun N-terminal kinase axis resulting in the activation of paxillin, NF-κB, and matrix metalloproteinase-2 (MMP-2). MDA-9/syntenin physically interacts with c-Src through its PDZ binding motif following stimulation of melanoma cells with rFVIIa and FX. We also document that induction of this signaling pathway is required for TF·FVIIa·Xa-induced cell migration, invasion, and metastasis by melanoma cells. The present finding uncovers a novel role of MDA-9/syntenin as an important TF·FVIIa·Xa/PAR-1-regulated gene that initiates a signaling circuit essential for cell motility and invasion of metastatic melanoma. In these contexts, targeting TF·FVIIa·Xa and its relevant downstream targets such as MDA-9/syntenin, may represent a novel therapeutic strategy to control the evolution of neoplastic cells.
authors.affiliation: From the EA 4174, Onco-Hematology Unit, University Claude Bernard, INSERM, Lyon 1, 69372 Lyon, France.
authors.forename: Hanaa
authors.initials: H
authors.lastname: Aissaoui
authors.affiliation: From the EA 4174, Onco-Hematology Unit, University Claude Bernard, INSERM, Lyon 1, 69372 Lyon, France.
authors.forename: Célia
authors.initials: C
authors.lastname: Prévost
authors.affiliation: the Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland, and.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Boucharaba
authors.affiliation: the Transplantation and Clinical Immunology Department, Edouart Herriot Hospital, Lyon, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Sanhadji
authors.affiliation: From the EA 4174, Onco-Hematology Unit, University Claude Bernard, INSERM, Lyon 1, 69372 Lyon, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Bordet
authors.affiliation: From the EA 4174, Onco-Hematology Unit, University Claude Bernard, INSERM, Lyon 1, 69372 Lyon, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Négrier
authors.affiliation: From the EA 4174, Onco-Hematology Unit, University Claude Bernard, INSERM, Lyon 1, 69372 Lyon, France, habib.boukerche@univ-lyon1.fr.
authors.forename: Habib
authors.initials: H
authors.lastname: Boukerche
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D015942:Factor VIIa / Q000378:metabolism*; D005170:Factor X / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D054731:PDZ Domains; D051419:Paxillin / Q000378:metabolism; D011485:Protein Binding; D044463:Receptor, PAR-1 / Q000378:metabolism; D015398:Signal Transduction; D053676:Syntenins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D051419:Paxillin; D044463:Receptor, PAR-1; C109621:SDCBP protein, human; D053676:Syntenins; D005170:Factor X; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D015942:Factor VIIa; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
keywords: Adaptor Protein; Cell Invasion; Cell Migration; Melanoma; PDZ Domain; Tissue Factor