RETRACTED: <i>mda-9</i>/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB

Boukerche, Habib; Su, Zao-zhong; Emdad, Luni; Sarkar, Devanand; Fisher, Paul B.

doi:10.1158/0008-5472.can-06-3875

Cited by 79 publications

(90 citation statements)

References 46 publications

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“…We next manipulated the expression levels of mda-9/syntenin in FM516-SV and M4Beu., with low metastatic potential, and T1P26 and 7GP, which generate a high frequency of spontaneous metastasis in immunosuppressed neonatal rats (9,17,18). As evident in Fig.…”

Section: Forced Expression or Inhibition Of Expression Of Mda-9/syntementioning

confidence: 74%

“…Theoretically, binding of MDA-9/syntenin to c-Src through its PDZ domain-binding motifs may enable MDA-9/syntenin to assemble large c-Src-FAK complexes, which greatly enhance activation of the c-Src-FAK complex, leading to amplification of p38/NF-B signaling pathways (7)(8)(9). In this study, we observed that stimulation of integrin signaling with fibronectin, which recruits the SH3 domain of c-Src to the cytoplasmic domain of integrin and eventually leads to c-Src activation (28), promoted the formation of an active c-Src-FAK signaling complex in melanoma cells overexpressing mda-9/syntenin from the small pool of c-Src proteins with which FAK was associated (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We previously documented that such changes orchestrated by the actin cytoskeleton lead to an increase in anchorage-independent growth and invasiveness of melanoma cells in a FAK-dependent manner that involve activation of key signaling molecules, including p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPK) (4). Recent studies demonstrate that mda-9/syntenin induces NF-B activation, representing a potential mechanism by which mda-9/syntenin acting through FAK promotes cancer progression to metastasis in an MMP-2-dependent manner (9). However, it is unclear precisely how mda-9/syntenin holds multiprotein signaling complexes together or how these complexes impact the cells' migration machinery.…”

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confidence: 99%

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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.

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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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Section: Forced Expression or Inhibition Of Expression Of Mda-9/syntementioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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.

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118

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“…However, the signaling pathways underlying MMP-2 expression and activation, as induced by d-GM3, have not been elucidated. Activation of p38 signaling mediates transcriptional activation of MMP-2 and MMP-9 (36,37), but the role of p38 in tumor metastasis is controversial (for reviews, refs. 19,21,38].…”

Section: Discussionmentioning

confidence: 99%

“…The expression of GAPDH was used as an internal control; C, the effects of uPAR expression on the expression and phosphorylation of FAK, Src, and PI3K were examined by immunoblotting. uPAR was either knocked down with 3 independent siRNA sequences (Table 1) pathway is likely involved in tumor suppression by negatively regulating cell survival and proliferation (21,38), it has been suggested that p38 can positively regulate cell adhesion, invasion, and metastasis in tumors, including melanomas (32,36,37,(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Deacetylated GM3 Promotes uPAR-Associated Membrane Molecular Complex to Activate p38 MAPK in Metastatic Melanoma

Qiu

Bach

Gatla

et al. 2013

Molecular Cancer Research

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GM3, the simplest ganglioside, regulates cell proliferation, migration, and invasion by influencing cell signaling at the membrane level. Although the classic N-acetylated form of GM3 (NeuAcLacCer) is commonly expressed and has been well studied, deacetylated GM3 (NeuNH 2 LacCer, d-GM3) has been poorly investigated, despite its presence in metastatic tumors but not in noninvasive melanomas or benign nevi. We have recently found that d-GM3 stimulates cell migration and invasion by activating urokinase plasminogen activator receptor (uPAR) signaling to augment matrix metalloproteinase-2 (MMP-2) function. However, the mechanisms by which d-GM3/ uPAR increase MMP-2 expression and activation are not clear. By modifying the expression of d-GM3 genetically and biochemically, we found that decreasing d-GM3 expression inhibits, whereas overexpressing d-GM3 stimulates, p38 mitogen-activated protein kinase (MAPK) activity to influence MMP-2 expression and activation. p38 MAPK (p38) activation requires the formation of a membrane complex that contains uPAR, caveolin-1, and integrin a5b1 in membrane lipid rafts. In addition, knocking down or inhibiting focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), or Src kinase significantly reduces d-GM3-induced p38 phosphorylation and activation. Taken together, these results suggest that d-GM3 enhances the metastatic phenotype by activating p38 signaling through uPAR/integrin signaling with FAK, PI3K, and Src kinase as intermediates. Elucidation of the mechanisms by which d-GM3, a newly discovered, potential biomarker of metastatic melanomas, promotes cell metastasis will help us to understand the function of d-GM3 in metastatic melanomas and may lead to novel GM3-based cancer therapies. Mol Cancer Res; 11(6); 665-75. Ó2013 AACR. IntroductionAlthough recent therapeutic progress for metastatic melanomas has significantly improved, including the more recent availability of small-molecule inhibitors targeting BRAF mutation or both BRAF mutation and MEK, or anti-CTLA4 antibody, survival is minimally prolonged and mortality rate of metastatic melanomas remains high (1-3). It is of utmost importance to discover specific molecular biomarkers that can distinguish melanomas with metastatic propensity from more indolent ones, which will improve prognostication, allow for earlier and more efficacious treatments, and provide additional targets for novel therapy.

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Melanoma differentiation associated gene‐9/syndecan binding protein promotes hepatocellular carcinoma

et al. 2022

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Background and Aims: The oncogene Melanoma differentiation associated gene‐9/syndecan binding protein (MDA‐9/SDCBP) is overexpressed in many cancers, promoting aggressive, metastatic disease. However, the role of MDA‐9 in regulating hepatocellular carcinoma (HCC) has not been well studied. Approach and Results: To unravel the function of MDA‐9 in HCC, we generated and characterized a transgenic mouse with hepatocyte‐specific overexpression of MDA‐9 (Alb/MDA‐9). Compared with wild‐type (WT) littermates, Alb/MDA‐9 mice demonstrated significantly higher incidence of N‐nitrosodiethylamine/phenobarbital‐induced HCC, with marked activation and infiltration of macrophages. RNA sequencing (RNA‐seq) in naive WT and Alb/MDA‐9 hepatocytes identified activation of signaling pathways associated with invasion, angiogenesis, and inflammation, especially NF‐κB and integrin‐linked kinase signaling pathways. In nonparenchymal cells purified from naive livers, single‐cell RNA‐seq showed activation of Kupffer cells and macrophages in Alb/MDA‐9 mice versus WT mice. A robust increase in the expression of Secreted phosphoprotein 1 (Spp1/osteopontin) was observed upon overexpression of MDA‐9. Inhibition of NF‐κB pathway blocked MDA‐9–induced Spp1 induction, and knock down of Spp1 resulted in inhibition of MDA‐9–induced macrophage migration, as well as angiogenesis. Conclusions: Alb/MDA‐9 is a mouse model with MDA‐9 overexpression in any tissue type. Our findings unravel an HCC‐promoting role of MDA‐9 mediated by NF‐κB and Spp1 and support the rationale of using MDA‐9 inhibitors as a potential treatment for aggressive HCC.

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

Cited by 79 publications

References 46 publications

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

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

Deacetylated GM3 Promotes uPAR-Associated Membrane Molecular Complex to Activate p38 MAPK in Metastatic Melanoma

Melanoma differentiation associated gene‐9/syndecan binding protein promotes hepatocellular carcinoma

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