Tumor necrosis factor-α (TNF-α) stimulates the epithelial-mesenchymal transition regulator Snail in cholangiocarcinoma

Epithelial-mesenchymal transition (EMT) is a series of events during which epithelial cells lose many of their epithelial characteristics and take on properties that are typical of mesenchymal cells that lack cell-cell adhesion properties. EMT may be activated by various types of growth factors or inflammatory cytokines. In many types of epithelial cancers, the EMT-derived tumor cells are susceptible to metastasis. During tumor progression, epithelial cells acquire a gene expression pattern closely resembling that of mesenchymal cells. This study aimed to investigate the expression of the EMT-associated transcription factor Snail and an adhesion molecule E-cadherin in cholangiocarcinoma (CCA) tissues. The effect of TNF-alpha on EMT activation in CCA cells was also demonstrated. The qRT-PCR analysis revealed that Snail expression significantly increased in CCA (P = 0.01) and was correlated with tumor metastasis (P = 0.02). The expression of Snail was inversely associated with E-cadherin (P = 0.004). The stimulation of TNF-alpha enhances migration behavior and showed significantly induced expression of Snail in CCA cell lines, whereas expression of E-cadherin and CK-19 (the epithelial marker) was reduced. Immunofluorescence analysis revealed that TNF-alpha-treated CCA cell lines increased nuclear translocation of Snail, whereas E-cadherin was dramatically decreased. Our findings suggest that the changes in the expression of Snail or E-cadherin might regulate EMT development in CCA resulting in promoting tumor progression. Overexpression of Snail could be used as a prognostic marker for monitoring the treatment efficiency of CCA patients.