Snail‐associated epithelial–mesenchymal transition promotes oesophageal squamous cell carcinoma motility and progression

Abstract

The essential contribution of the epithelial-mesenchymal transition (EMT) to carcinoma progression is the loss of their epithelial characters, gain of mesenchymal marker expression, acquisition of migration, invasive activity and capability to pass through the basement membrane. In this study, we aimed to clarify the role of EMT regulator Snail, a zinc finger transcription factor, in human oesophageal squamous cell carcinoma (OESCC). Most OESCC cell lines expressed epithelial cell-cell adhesion molecules such as E-cadherin and claudin-1 and -7; however, TE-8 (Snail-positive) cells expressed mesenchymal marker vimentin but not E-cadherin and claudins. Transduction of ectopic Snail in TE-15 (Snail-negative) cells diminished expression of these epithelial adhesion molecules with promotion of cell migration, invasion and proliferation as well as the shift from cobblestone-like appearance to spindle morphology. In OESCC tissue samples, immunohistochemical analyses revealed that the nuclear Snail expression at the invasive front was correlated with the high levels of vimentin expression (p = 0.0061), which was conversely associated with reduced expressions of E-cadherin (p = 0.023), claudin-1 (p = 0.0246) and claudin-7 (p = 0.0161). Interestingly, elevated Snail expression at the invasive front of the OESCC was associated with higher incidence of lymphatic (p = 0.0143) and venous vessels invasion (p = 0.0029), lymph node metastasis (p = 0.0074) and clinicopathological tumour stage (p = 0.0057). According to the expressions of epithelial and mesenchymal markers, the tumours were subclassified into three groups, the epithelial-type OESCC and the complete or incomplete EMT-type OESCCs. Snail-positive tumours were frequently categorized into the complete- or incomplete-type EMT phenotypes. Our present results suggest the significance of Snail-associated EMT in the progression of OESCC. Snail-induced EMT at the invasive front of the OESCC can be a novel marker for the prediction of metastasis.