Slug contributes to cadherin switch and malignant progression in muscle-invasive bladder cancer development

Objectives: The Snail family of zinc finger transcription factors (i.e., Snail and Slug) predicts the tumor recurrence in superficial bladder cancers, while their roles in the development of muscle-invasion, metastasis, and chemoresistance in muscle-invasive bladder cancers with poor prognosis have not been investigated. This study evaluates the clinical significance of Slug in aggressive bladder cancer. Materials and methods: A pair of sublines (i.e., T24-P and T24-L) from a unique orthotropic metastatic model of bladder cancer was firstly utilized to identify the potential precursors contributing to those aggressive phenotypes. The coexpression of Slug, E-cadherin, and N-cadherin in bladder cancer cell lines (i.e., 5637, RT4, 253 J, J82, and T24) and tissues was evaluated by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry staining analysis. The function of Slug expression on E- to N-cadherin switch, cell invasion, and chemoresistance to proapoptotic treatment was validated by gain-in-function and knockdown strategy in vitro. Results: Slug was identified as one of the novel targets contributed to the aggressive phenotypes of T24-L cells, which showed enhanced cell invasive, metastatic, and chemoresistant potentials in vitro and in vivo as previously described. Up-regulation of Slug was significantly correlated with a higher tumor stage and the E- to N-cadherin switch in bladder cancer cells and tissues, whereas ectopic expression of Slug in bladder cancer 5637 and RT-4 cell lines promoted epithelial-to-mesenchymal transition (EMT), increased cell invasiveness and chemoresistance. By contrast, knocking down Slug using siRNA in T24-L cell lines reversed these changes. Conclusions: Slug elevates in invasive or metastatic bladder cancer and plays a critical role in EMT via control of cadherin switch. Slug may be a potential marker or target for improving the diagnosis and treatment of muscle-invasive bladder cancers.