Slug is a downstream mediator of transforming growth factor‐β1‐induced matrix metalloproteinase‐9 expression and invasion of oral cancer cells

Joseph, Mathew J.; Dangi-Garimella, Surabhi; Shields, Mario A.; Diamond, Michelle E.; Sun, Limin; Koblinski, Jennifer E.; Munshi, Hidayatullah G.

doi:10.1002/jcb.22309

Cited by 84 publications

(95 citation statements)

References 55 publications

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“…Indeed, Slug overexpression is an indicator of poor overall survival in patients with lung cancer and, in agreement with our observations, Slug promotes invasion of lung cancer cells in vitro and in mouse models (13). Moreover, it was shown that Slug facilitates invasion of both pancreatic and oral cancer cells through upregulation of MMP-9 (24,25). In addition, Vuoriluoto and colleagues previously demonstrated that Slug induces vimentin expression and migration in mammary cells (26).…”

Section: Discussionsupporting

confidence: 90%

Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Joannes

Grelet

Duca

et al. 2014

Molecular Cancer Research

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In many cancers, including lung carcinomas, Fragile histidine triad (Fhit) is frequently decreased or lost. Fhit status has recently been shown to be associated with elevated in vitro and in vivo invasiveness in lung cancer. Tumor cell invasion is facilitated by epithelial-mesenchymal transition (EMT), a process by which tumor cells lose their epithelial features to acquire a mesenchymal cell-like phenotype. In this study, the mechanism underlying Fhitregulated EMT was deciphered. Using Slug knockdown, pharmacologic inhibitors PD98059, PP1, and gefitinib as well as an anti-EGFR antibody, it was demonstrated that Fhit silencing in bronchial cells induced overexpression of two primary EMT-associated targets, MMP-9 and vimentin, to regulate cell invasion dependent on an EGFR/Src/ ERK/Slug signaling pathway. Moreover, ectopic expression of Fhit in Fhit-deficient lung cancer cells downregulated this pathway. Finally, an inverse correlation was observed between Fhit and phospho-EGFR levels in a cohort of human squamous cell lung carcinoma specimens. These results demonstrate a Fhit-dependent mechanism in the control of EMT-regulated EGFR signaling.

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Section: Discussionsupporting

confidence: 90%

Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Joannes

Grelet

Duca

et al. 2014

Molecular Cancer Research

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“…It was recently reported that hundreds of proteins are under ERK-dependent control (20). Snai2 belongs to the Snail family of zinc-finger transcription factors, and is a well-established downstream target of the MAPK/ERK pathway in a number of cell types (21,22). Our previous study (23) demonstrated that the MAPK-Snai2 pathway played an important role in salivary adenoid cystic carcinoma (SACC) metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Snail family genes are also best known for their role in epithelial-to-mesenchymal transition (EMT) (24). In several types of human cancer, there is an inverse association between E-cadherin and Snail gene family expression (22,25,26). Wang et al (27) confirmed that Snai2 overexpression was correlated with reduced E-cadherin expression and enhanced vimentin expression in two independent cohorts of TSCC patients.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II type 2 receptor-interacting protein 3a suppresses proliferation, migration and invasion in tongue squamous cell carcinoma via the extracellular signal-regulated kinase-Snai2 pathway

Zhao

et al. 2015

Oncology Letters

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Abstract.Our previous studies demonstrated that the downregulation of microtubule-associated tumor suppressor 1/angiotensin II type 2 receptor-interacting protein (MTUS1/ATIP) is associated with poor differentiation and prognosis in tongue squamous cell carcinoma (TSCC), and that ATIP1 exerts an antiproliferative effect on TSCC. The aim of the present study was to further investigate the anticancer effect of MTUS1/ATIP3a in TSCC. It was observed that UM1 cells (a TSCC cell line with high migration and invasion ability) exhibited lower expression of ATIP3a compared with UM2 cells (a TSCC cell line with lower migration and invasion ability). Restoration of ATIP3a expression in UM1 cells exerted antiproliferative effects and inhibited migration and invasion, whereas knockdown of ATIP3a promoted proliferation, migration and invasion in UM2 cells. Restoration of ATIP3a expression inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and the expression of Snai2 and vimentin in UM1 cells, whereas knockdown of ATIP3a promoted the phosphorylation of ERK1/2 and the expression of Snai2 and vimentin in UM2 cells. Therefore, MTUS1/ATIP3a was found to suppress the proliferation, migration and invasion of TSCC cells via the ERK1/2-Snai2 pathway.

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“…Generation of MT1-MMP-inducible OKF6 and SCC25 CellsThe coding sequence for the full-length MT1-MMP, the catalytically inactive EA, and the tail-deleted DC mutants of MT1-MMP have been described previously (30) and were subcloned into pRetroX-Tight-Pur vector (33). All plasmids were verified by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Dangi-Garimella

Redig

Shields

et al. 2010

Journal of Biological Chemistry

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Matrix metalloproteinases (MMPs) 2 are a large family of highly conserved metalloendopeptidases with proteolytic activity directed against a variety of extracellular matrix (ECM) substrates (1-3). MMPs have been implicated in basement membrane proteolysis, activation of growth factors, and cleavage of cell-adhesion molecules. Extending mechanistic investigation to cancer biology, numerous studies have shown that MMP overexpression enhances the invasive activity of tumor cell lines (4 -6). Analysis of human disease further supports the pro-tumorigenic role of MMPs, as increased expression of these proteases in tumor samples is clinically associated with invasion, metastasis, poor prognosis, and shorter survival times (7,8). In the specific case of squamous cell carcinoma (SCC), increased expression of membrane type 1-MMP (MT1-MMP, MMP14) is associated with ECM breakdown, tissue invasion, and lymph node metastasis (8).However, several animal studies have now clearly demonstrated that multiple members of the MMP family provide a paradoxically protective effect during the relentless molecular destruction that characterizes malignant progression. MMPs may have been initially identified as potent pro-tumorigenic proteases, but their simultaneous ability to function in an opposing, anti-tumorigenic role is now equally well established (9, 10). Such data underscore both the complexity of MMP activity in cellular signaling events as well as the importance of stringently evaluating the context in which these proteases take on either an anti-tumorigenic or pro-tumorigenic role. Intriguingly, several recent studies using SCC models have begun to suggest a putative mechanism through which MMPs may be induced to function primarily as anti-tumorigenic proteases. When exposed to carcinogens, MMP3-null mice developed squamous cell skin cancers that not only grew faster but were also strikingly less differentiated than those of control animals (11). Significantly, orthotopic injection of MMP3-expressing tumor cells resulted in pronounced tumor cell differentiation (12). However, although such findings indicate that MMPs may inhibit SCC progression by promoting tumor cell differentiation, the precise mechanism through which these proteinases regulate this process has not yet been elucidated.In normal tissue keratinocyte differentiation is a complex process mediated by cell-ECM and cell-cell interactions that subsequently activate downstream signaling pathways (13-15). Specifically, among structural proteins, integrins mediate primarily cell-ECM interactions, whereas cadherins are responsible for cell-cell interactions (13). In vitro activation of integrins or inhibition of cadherins after ligation or dominant negative expression, respectively, results in negative regulation of human keratinocyte differentiation (16 -18). Furthermore, beyond structural proteins, Rho GTPases are also known to be an important component of keratinocyte differentiation pathways. Rho signaling has been shown to mediate cell-cell and cell-matrix adhesion...

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Slug is a downstream mediator of transforming growth factor‐β1‐induced matrix metalloproteinase‐9 expression and invasion of oral cancer cells

Cited by 84 publications

References 55 publications

Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Angiotensin II type 2 receptor-interacting protein 3a suppresses proliferation, migration and invasion in tongue squamous cell carcinoma via the extracellular signal-regulated kinase-Snai2 pathway

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

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