Slug (SNAI2) expression in oral SCC cells results in altered cell-cell adhesion and increased motility

Oral Biology Department, College of Dentistry, The University of Nebraska Medical Center, Lincoln, NE, USA.
Cell adhesion & migration (Impact Factor: 4.51). 07/2011; 5(4):315-22. DOI: 10.4161/cam.5.4.17040
Source: PubMed


The Snail family of zinc finger transcription factors plays an important role in epithelial to mesenchymal transition (EMT) in a variety of tissues and systems. Slug (SNAI2) expression has been shown to directly contribute to a subset of events required for EMT in events such as re-epithelialization during wound healing and neural crest cell migration. In addition, slug expression was shown to correlate with disease recurrence in head and neck squamous cell carcinoma (HNSCC) patients. Based on this association we chose to specifically examine the effects of exogenous slug expression in HNSCC cells and specifically assess adhesive junction assembly and the motility characteristics in these cells. Slug expression led to changes in adherens junction and desmosome assembly characterized by a classical cadherin switch and loss of desmosome assembly. Additionally, we performed gene expression profiling to identify novel slug dependent gene expression changes in a HNSCC cell line. In addition to genes known to be altered during EMT, we identified a novel set of Slug responsive genes that will provide a better understanding of slug overexpression during EMT and HNSCC progression.

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Available from: James K Wahl III, Oct 09, 2014
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    • "Tumor cells at the invasive front often undergo EMT and exhibit high motility (Christofori, 2006). The EMT transcription factors Snail, Slug, and Twist-1 all upregulate/induce LMα4 in tumor cells (Takkunen et al., 2008; Mikheeva et al., 2010; Katafiasz et al., 2011). Moreover, FOXM1, a transcription factor which is overexpressed in most human cancers and contributes to tumor progression, EMT, invasion and metastasis, positively regulates laminin α4 chain expression (Kim et al., 2005; Halasi and Gartel, 2013; Wierstra, 2013). "
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    ABSTRACT: α4-laminins, such as laminins 411 and 421, are mesenchymal laminins expressed by blood and lymphatic vessels and some tumor cells. Laminin-411 promotes migration of leukocytes and endothelial cells, but the effect of this laminin and laminin-421 on tumor cells is poorly understood. In the present study, we demonstrate that laminin-411 and, to a greater extent, laminin-421 significantly promote migration of tumor cells originated from melanomas, gliomas and different carcinomas via α6β1 integrin. In solid-phase binding assays, both laminins similarly bound α6β1 integrin but only laminin-421, among several laminin isoforms, readily bound MCAM (CD146), a cell-surface adhesion molecule strongly associated with tumor progression. Accordingly, a function-blocking mAb to MCAM inhibited tumor cell migration on laminin-421 but not on laminins 411 or 521. In tumor tissues, melanoma cells co-expressed MCAM, laminin α4, β1, β2 and γ1 chains, and integrin α6 and β1 chains. The present data highlight the novel role of α4-laminins in tumor cell migration and identify laminin-421 as a primary ligand for MCAM and a putative mediator of tumor invasion and metastasis.
    Full-text · Article · Jun 2014 · Matrix biology: journal of the International Society for Matrix Biology
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    • "This is the first report of the direct relationship between Snail transcription factor and retinal pigment epithelial–mesenchymal transition. EMT is a well characterized process defined morphologically as the conversion of epithelial cells to a fibroblast or mesenchymal morphology and is known to be dependent on the Snail family of transcription factors [3] [19] [20] "
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    ABSTRACT: Snail transcription factor has been implicated as an important regulator in epithelial-mesenchymal transition (EMT) during tumourigenesis and fibrogenesis. Our previous work showed that Snail transcription factor was activated in transforming growth factor β1 (TGF-β1) induced EMT in retinal pigment epithelial (RPE) cells and may contribute to the development of retinal fibrotic disease such as proliferative vitreoretinopathy (PVR). However, whether Snail alone has a direct role on retinal pigment epithelial-mesenchymal transition has not been investigated. Here, we analyzed the capacity of Snail to drive EMT in human RPE cells. A vector encoding Snail gene or an empty vector were transfected into human RPE cell lines ARPE-19 respectively. Snail overexpression in ARPE-19 cells resulted in EMT, which was characterized by the expected phenotypic transition from a typical epithelial morphology to mesenchymal spindle-shaped. The expression of epithelial markers E-cadherin and Zona occludin-1 (ZO-1) were down-regulated, whereas mesenchymal markers a-smooth muscle actin (a-SMA) and fibronectin were up-regulated in Snail expression vector transfected cells. In addition, ectopic expression of Snail significantly enhanced ARPE-19 cell motility and migration. The present data suggest that overexpression of Snail in ARPE-19 cells could directly trigger EMT. These results may provide novel insight into understanding the regulator role of Snail in the development of retinal pigment epithelial-mesenchymal transition.
    Full-text · Article · Mar 2014 · Biochemical and Biophysical Research Communications
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    • "reported to alter cadherins in one NHSCC cell line [4], whether Slug has a stable effect and plays a necessary role in hypoxia induced cadherin switch in NHSCC remains unclear. Moreover, Slug has been reported to be associated with poor survival in some carcinomas [11] [12] [13] [14], even though little is known regarding the role of Slug in predicting HNSCC outcomes. "
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    ABSTRACT: According to recent studies, the function of Slug in hypoxia induced cadherin switch differs from cancer to cancer. Whether Slug is an essential mediator of the tumor hypoxia induced cadherin switch in head and neck squamous cell carcinoma (HNSCC) and the prognostic role of Slug in HNSCC patients are not elucidated. The aim of this study is to investigate the role of the Slug in cadherin switch induced by hypoxia in HNSCC. Two HNSCC cell lines and 119 HNSCC specimens were selected for the present experiments. E/N-cadherins expression and tumor cell invasion responding to hypoxia/HIF-1α overexpression and the silence of Slug/SnaI2 gene were detected in vitro. HNSCC specimens were analyzed by immunohistochemistry staining to correlate the expressions of Slug, HIF-1α and E/N-cadherins with clinical outcomes. Our research evidenced that Slug was extremely elevated in the HNSCC cells in response to hypoxia/HIF-1α overexpression. Suppressing Slug expression impaired HIF-1α induced cadherin switch and tumor invasion. In HNSCC tissues, relatively high expression of Slug was detected to be associated with endogenous HIF-1α overexpression, cadherin switch, the risk of lymph node metastasis, and a more advanced TNM stage. Additionally, aberrant Slug expression combined with HIF-1α overexpression and cadherin switch was significantly correlated with shorter HNSCC patient survival. In conclusion, Slug is necessary for hypoxia-induced cadherin switch in HNSCC and may be used as a potential risk marker in predicting HNSCC clinical outcomes.
    Full-text · Article · Sep 2013 · Oral Oncology
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