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: Hanaa Aissaoui, Célia Prévost, Ahmed Boucharaba, Kamel Sanhadji, Jean-Claude Bordet, Claude Négrier, Habib Boukerche
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 6 Pg. 3333-48 (Feb 06 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 25505176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• NF-kappa B
• Paxillin
• Receptor, PAR-1
• SDCBP protein, human
• Syntenins
• Factor X
• src-Family Kinases
• JNK Mitogen-Activated Protein Kinases
• Factor VIIa
• MMP2 protein, human
• Matrix Metalloproteinase 2
• cdc42 GTP-Binding Protein
• rac1 GTP-Binding Protein

Topics

• Animals
• Cell Line, Tumor
• Cell Movement
• Factor VIIa (metabolism)
• Factor X (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Melanoma (metabolism, pathology)
• Mice
• NF-kappa B (metabolism)
• NIH 3T3 Cells
• Neoplasm Metastasis
• PDZ Domains
• Paxillin (metabolism)
• Protein Binding
• Receptor, PAR-1 (metabolism)
• Signal Transduction
• Syntenins (chemistry, genetics, metabolism)
• Up-Regulation
• cdc42 GTP-Binding Protein (metabolism)
• rac1 GTP-Binding Protein (metabolism)
• src-Family Kinases (metabolism)