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.
Highlights
Melanoma differentiation associated gene-9 (MDA-9)/syntenin and tissue factor (TF) are overexpressed in most types of human cancer
These findings suggest that TF expressed on these metastatic cells is functionally active and its expression correlates with the expression levels of MDA-9/syntenin and the metastatic potential of melanoma cells
Recombinant factor VIIa (FVIIa) and Xa Induces MDA-9/Syntenin Expression in Human Melanoma Cells—To test the hypothesis that FVIIa binding to TF in melanoma cells may regulate the expression of endogenous MDA-9/syntenin, serum-starved metastatic cell lines, T1P26, 7GP, and c8161 were treated with rFVIIa for 60 min
Summary
MDA-9/syntenin and tissue factor (TF) are overexpressed in most types of human cancer. Results: Induction of MDA-9/syntenin in melanoma involves the binding of FVIIa and FX to TF on the cell surface, which initiates a signaling circuit essential for cell motility and metastasis of 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 Rac and Cdc42/c-Jun N-terminal kinase axis resulting in the activation of paxillin, NF-B, and matrix metalloproteinase-2 (MMP-2). The present finding uncovers a novel role of MDA-9/syntenin as an important TF1⁄7FVIIa1⁄7Xa/PAR-1-regulated gene that initiates a signaling circuit essential for cell motility and invasion of metastatic melanoma. In these contexts, targeting TF1⁄7FVIIa1⁄7Xa and its relevant downstream targets such as MDA-9/syntenin, may represent a novel therapeutic strategy to control the evolution of neoplastic cells
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