title: Slug contributes to cadherin switch and malignant progression in muscle-invasive bladder cancer development.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, P.R. China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, Xi'an, P.R. China.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Wu
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhou
authors.forename: Jinhai
authors.initials: J
authors.lastname: Fan
authors.forename: Yule
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: TingTing
authors.initials: T
authors.lastname: Zhang
authors.forename: Xinyang
authors.initials: X
authors.lastname: Wang
authors.forename: Dalin
authors.initials: D
authors.lastname: He
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009132:Muscles / Q000473:pathology; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D015820:Cadherins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors