Melanoma metastasis is associated with enhanced expression of the syntenin gene

Helmke, Burkhard; Polychronidis, Myriam; Benner, Axel; Thome, Marianne; Arribas, Joaquín; Deichmann, Martin

doi:10.3892/or.12.2.221

Cited by 31 publications

(40 citation statements)

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“…The involvement of syntenin-1 in T cell migration is in agreement with other observations indicating that syntenin-1 might be an important determinant of the malignant phenotype of epithelial cancers (Helmke et al, 2004;Sarkar et al, 2004;Boukerche et al, 2005). Moreover, M-RIP silencing has been reported to inhibit cell invasivity (Ono et al, 2008) and to lie downstream of TGF-b during breast cancer dissemination (Giampieri et al, 2009), so the syntenin-1-M-RIP axis might also be relevant for tumor cell migration.…”

Section: Discussionsupporting

confidence: 78%

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions

Sala-Valdés

Gordon-Alonso

Tejera

et al. 2012

Journal of Cell Science

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SummaryIn this study, we describe that the PDZ protein syntenin-1 is a crucial element for the generation of signaling asymmetry during the cellular response to polarized extracellular cues. We analyze the role of syntenin-1 in the control of asymmetry in two independent models of T cell polarization -the migratory response to chemoattractants and the establishment of cognate interactions between T cells and antigenpresenting cells (APCs). A combination of mutant, biochemical and siRNA approaches demonstrate that syntenin-1 is vital for the generation of polarized actin structures such as the leading edge and the contact zone with APCs. We found that the mechanism by which syntenin-1 controls actin polymerization relies on its mandatory role for activation of the small GTPase Rac. Syntenin-1 controls Rac through a specific association with the myosin phosphatase Rho interacting protein (M-RIP), which occurs in response to phosphorylation of syntenin-1 by Src at Tyr4. Our data indicate the key role of syntenin-1 in the generation of functional asymmetry in T cells and provide a novel mechanistic link between receptor activation and actin polymerization and accumulation in response to extracellular stimulation.

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Section: Discussionsupporting

confidence: 78%

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions

Sala-Valdés

Gordon-Alonso

Tejera

et al. 2012

Journal of Cell Science

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“…This increase was attenuated by treatment with PP2 or siRNA knockdown of c-Src, suggesting that c-Src bound to MDA-9/ syntenin functionally cooperates with FAK-induced activation of the p38 MAPK/NF-B signaling pathways to promote migration of melanoma cells (9). The functional cooperation between MDA-9/ syntenin and c-Src in human cancer is supported by a number of reports showing that cancer progression in multiple cancers is associated with enhanced expression of mda-9/syntenin in which c-Src activity is frequently elevated (4)(5)(6)(7)(8)12). In these contexts, our present studies support a central role for mda-9/syntenin in the c-Src-FAK axis that regulates migration/invasion of melanoma cells (29).…”

Section: Discussionmentioning

confidence: 49%

“…These changes are consistent with early enhancement followed by decreased expression during the course of reversion of the cancer phenotype in melanoma cells (2,3). mda-9, also called syntenin, expression displays an inverse relationship with tumor progression, with lowlevel expression in melanocytes and radial growth phase (RGP) primary melanoma versus elevated expression in vertical growth phase (VGP) primary melanoma and metastatic melanomas (4,5). The level of mda-9/syntenin is also elevated in multiple additional cancers, including breast and gastric carcinomas, suggesting an expanded involvement in tumor progression (6).…”

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confidence: 67%

mda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src

Boukerche

Prévot

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

118

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The scaffold PDZ-domain containing protein mda-9/syntenin functions as a positive regulator of cancer cell progression in human melanoma and other tumors. mda-9/Syntenin regulates cell motility and invasion by altering defined biochemical and signaling pathways, including focal adhesion kinase (FAK), p38 mitogenactivated protein kinase (MAPK) and NF-B, but precisely how mda-9/syntenin organizes these multiprotein signaling complexes is not well understood. Using a clinically relevant human melanoma model, we demonstrate that mda-9/syntenin physically interacts with c-Src and this communication correlates with an increase in FAK/c-Src complex formation and c-Src activation. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin or addition of c-Src siRNA, suppresses melanoma cell migration, anchorage-independent growth, and spontaneous tumor cell dissemination in vivo in a human melanoma animal metastasis model. These data are compatible with a model wherein interaction of MDA-9/syntenin with c-Src promotes the formation of an active FAK/c-Src signaling complex, leading to enhanced tumor cell invasion and metastatic spread. These provocative findings highlight mda-9/ syntenin and its interacting partners as promising therapeutic targets for intervention of metastasis. Understanding and preventing this process and its dire consequences remain formidable obstacles in achieving successful treatment outcomes in advanced cancer patients. In the context of advanced melanoma, the response rate of patients with metastatic disease to single agent chemotherapy or combination therapies is frequently less than 10% (1). Given this bleak picture, it is vital to develop new, efficacious, and rationally designed treatment strategies to, ideally, prevent or effectively treat metastasis. In this context, defining relevant genes that are seminal regulators of metastasis provide an entry point for developing improved therapies.Melanoma differentiation associated gene-9 (mda-9) was cloned in our laboratory (2, 3) as a unique gene displaying biphasic expression during terminal differentiation of human melanoma cells treated with a combination of fibroblast IFN (IFN-␤) and the antileukemic compound mezerein (MEZ). These changes are consistent with early enhancement followed by decreased expression during the course of reversion of the cancer phenotype in melanoma cells (2, 3). mda-9, also called syntenin, expression displays an inverse relationship with tumor progression, with lowlevel expression in melanocytes and radial growth phase (RGP) primary melanoma versus elevated expression in vertical growth phase (VGP) primary melanoma and metastatic melanomas (4, 5). The level of mda-9/syntenin is also elevated in multiple additional cancers, including breast and gastric carcinomas, suggesting an expanded involvement in tumor progression (6). Recently, we confirmed the importance of mda-9/syntenin in metastasis in vivo, providing direct support for mda-9/syntenin as an essential gene controlling melanoma progres...

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“…This hypothesis was tested recently and validated using a clinically relevant melanoma model (13,14) providing direct evidence that mda-9/syntenin promotes melanoma progression and metastasis in vivo (15). The biological significance of mda-9/syntenin in melanoma progression is supported by immunohistochemical studies showing that MDA-9/syntenin is expressed by an increasing proportion of primary melanomas in the transition from the radial to vertical growth phase (15,16). An intriguing property of mda-9/syntenin is its ability, when expressed by means of a replication-incompetent adenovirus (Ad.mda-9/S) in melanoma cells, to alter cytoskeletal organization, and increase focal adhesion kinase (FAK) phosphorylation and other signaling molecules, such as phospho-p38 and phospho-c-Jun NH 2 -terminal kinase (JNK), resulting in increased motility and invasive potential of melanoma cells (15).…”

Section: Introductionmentioning

confidence: 95%

mda-9/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB

Boukerche¹,

Su²,

Emdad³

et al. 2007

Cancer Research

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mda-9/Syntenin is a scaffolding PDZ domain-containing protein overexpressed in multiple human cancers that functions as a positive regulator of melanoma metastasis. Using a normal immortal human melanocyte cell line and weakly and highly metastatic human melanoma cell lines, we presently show that mda-9/syntenin initiates a signaling cascade that activates nuclear factor-KB (NF-KB) in human melanoma cells. As a consequence of elevated mda-9/syntenin expression, tumor cell growth and motility, fundamental components of tumor cell invasion and metastatic spread of melanoma cells, are enhanced through focal adhesion kinase (FAK)-induced and p38 mitogen-activated protein kinase (MAPK)-induced activation of NF-KB. Inhibiting mda-9/ syntenin, using an adenovirus expressing antisense mda-9/ syntenin, NF-KB, using an adenovirus expressing a mutant superrepressor of IKBA, or FAK, and using a dominantnegative mutant of FAK (FRNK), blocks melanoma cell migration, anchorage-independent growth, and invasion. Downstream signaling changes mediated by mda-9/syntenin, which include activation of FAK, p38 MAPK, and NF-KB, promote induction of membrane-type matrix metalloproteinase-1 that then activates pro-MMP-2-promoting migration and extracellular matrix invasion of melanoma cells. These results highlight the importance of mda-9/syntenin as a key component of melanoma metastasis providing a rational molecular target for potentially intervening in the metastatic process.

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Melanoma metastasis is associated with enhanced expression of the syntenin gene

Cited by 31 publications

References 0 publications

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions

mda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src

mda-9/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB

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