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1.
Cancer Res ; 73(2): 844-54, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23233738

ABSTRACT

Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chorioallantoic membrane (CAM) assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several proangiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/syntenin in which MDA-9/syntenin interacts with the extracellular matrix (ECM), activating Src and FAK resulting in activation by phosphorylation of Akt, which induces hypoxia inducible factor 1-α (HIF-1α). The HIF-1α activates transcription of insulin growth factor-binding protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell nonautonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (nonautonomous).


Subject(s)
Insulin-Like Growth Factor Binding Protein 2/metabolism , Melanoma/blood supply , Neovascularization, Pathologic/metabolism , Syntenins/metabolism , Animals , Cell Line, Tumor , Humans , Male , Mice , Mice, Nude , Syntenins/genetics , Transplantation, Heterologous
2.
Front Biosci (Landmark Ed) ; 17(1): 1-15, 2012 01 01.
Article in English | MEDLINE | ID: mdl-22201728

ABSTRACT

Melanoma differentiation associated gene-9 (MDA-9), synonymous with syntenin, is an adapter protein that provides a central role in regulating cell-cell and cell-matrix adhesion. MDA-9/syntenin transduces signals from the cell-surface to the interior through its interaction with a plethora of additional proteins and actively participates in intracellular trafficking and cell-surface targeting, synaptic transmission, and axonal outgrowth. Recent studies demarcate a seminal role of MDA-9/syntenin in cancer metastasis. In the context of melanoma, MDA-9/syntenin functions as a positive regulator of melanoma progression and metastasis through interactions with c-Src and promotes the formation of an active FAK/c-Src signaling complex leading to NF-k B and matrix metalloproteinase (MMP) activation. The present review provides a current perspective of our understanding of the important features of MDA-9/syntenin and its significant role in tumor cell metastasis with special focus on molecular mechanism of action.


Subject(s)
Melanoma/secondary , Syntenins/physiology , Enzyme Precursors/metabolism , Focal Adhesion Kinase 1/chemistry , Focal Adhesion Kinase 1/metabolism , Gelatinases/metabolism , Humans , Melanoma/pathology , Melanoma/physiopathology , Models, Biological , Multiprotein Complexes/chemistry , Nervous System/physiopathology , Protein Interaction Domains and Motifs , Proto-Oncogene Proteins pp60(c-src)/chemistry , Proto-Oncogene Proteins pp60(c-src)/metabolism , Signal Transduction , Syndecans/metabolism , Syntenins/chemistry , Syntenins/genetics , Tumor Suppressor Proteins/chemistry , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/physiology
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