title: Krüppel-like factor 4 is a novel prognostic predictor for urothelial carcinoma of bladder and it regulates TWIST1-mediated epithelial-mesenchymal transition.
abstract: Krüppel-like factor 4 (KLF4) exerts tumor suppressive or oncogenic functions in a cell-type-dependent manner, but its prognostic role in urothelial carcinoma of bladder (UCB) remains unclear. We aimed to determine how KLF4 regulates epithelial-mesenchymal transition (EMT) and predicts patient survival in UCB.
  
  
  
  The roles of KLF4 and other EMT regulators in cancer progression were studied in UCB specimens of 398 patients, UCB cell lines. The results were validated by open-access The Cancer Genome Atlas dataset.
  
  
  
  Over a median follow-up of 46.5 months, tissue microarray demonstrated that strong KLF4 expression was associated with higher risk toward metastasis and death (P<0.001). KLF4 expression positively correlated with TWIST1 and vimentin, and inversely correlated with E-cadherin expression. Metastasis-free survival was poorest in KLF4/TWIST1 coexpression group, followed by KLF4 or TWIST1 expression-alone group, and no-expression group (P<0.001). Multivariate analysis substantiated that KLF4/TWIST1 coexpression independently predicted overall mortality and metastasis risk with hazard ratios of 2.43 (95% CI: 1.65-3.64) and 7.54 (CI: 4.03-12.10). The Cancer Genome Atlas dataset of bladder cancer also revealed a trend toward decreased overall survival in the high KLF4 expression group as compared to the low KLF4 group. In vitro, KLF4 is accompanied with decreased E-cadherin and β-catenin expressions, increased vimentin and fibronectin expressions, and enhanced migration/invasion. KLF4 knockdown suppressed TWIST1 expression and inhibited EMT, migration and invasion, whereas enforced KLF4 overexpression activated TWIST1 expression and restored EMT and metastatic phenotype. Furthermore, TWIST1 knockdown abolished KLF4-faciliated EMT and metastatic feature without affecting KLF4 expression.
  
  
  
  KLF4 promotes TWIST1-mediated EMT and may represent a novel prognostic predictor in UCB.
authors: Division of Nephrology, Department of Medicine, Taipei City Hospital Heping-Fuyou Branch, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Wei-Cheng
authors: WC
authors: Tseng
authors: Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors: Cheng-Wei
authors: CW
authors: Chuang
authors: Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Muh-Hwa
authors: MH
authors: Yang
authors: Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Chin-Chen
authors: CC
authors: Pan
authors: Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Immunology Center, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: dctarng@vghtpe.gov.tw.
authors: Der-Cherng
authors: DC
authors: Tarng
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000032:analysis*; D015820:Cadherins / Q000096:biosynthesis; D002295:Carcinoma, Transitional Cell / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000032:analysis / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D011379:Prognosis; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D014746:Vimentin / Q000096:biosynthesis; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D005353:Fibronectins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D014746:Vimentin; D051176:beta Catenin
keywords: Epithelial-mesenchymal transition; Krüppel-like factor 4; TWIST1; Urothelial carcinoma of bladder