title: Epigenetic inactivation of KLF4 is associated with urothelial cancer progression and early recurrence.
abstract: OBJECTIVE
  KLF4 is a transcription factor with divergent functions in different malignancies. We analyzed KLF4 expression and DNA methylation, and their clinical relevance and biological function in urothelial cancer.
  
  
  METHODS
  Immunohistochemistry and Sequenom™ MassARRAY® were done to detect the expression and promoter methylation of KLF4 in urothelial cancer tissues. The association of the recurrence-free survival rate and decreased KLF4 or KLF4 methylation status was analyzed by the Kaplan-Meier method, Cox regression analysis and ROC assay. Lentivirus based KLF4 over expression and dsRNA mediated knockdown were used to detect KLF4 functions in urothelial cancer in vitro and in vivo.
  
  
  RESULTS
  KLF4 was down-regulated in urothelial cancer due to promoter hypermethylation. Each correlated with recurrence-free survival in patients with nonmuscle invasive bladder cancer after transurethral resection of bladder cancer, which potentiates them as valuable predictive biomarkers for early recurrence. Moreover, in and ex vivo experiments showed that KLF4 suppressed urothelial cancer cell growth, migration and invasion inhibited the epithelial-to-mesenchymal transition.
  
  
  CONCLUSIONS
  KLF4 may function as a tumor suppressor gene in urothelial cancer since down-regulation of KLF4 by promoter hypermethylation would promote cancer progression. In addition, decreased expression of KLF4 or its promoter hypermethylation may have predictive value for early recurrence in patients with nonmuscle invasive bladder cancer.
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Heng
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Urology and Helen-Diller Comprehensive Cancer Center, University of California-San Francisco, San Francisco, California.
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Ding
authors.initials: D
authors.lastname: Xia
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lang
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Zhiquan
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Zhangqun
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: xuhua@mail.hust.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D010386:Pelvic Neoplasms / Q000235:genetics / Q000473:pathology; D014516:Ureteral Neoplasms / Q000235:genetics / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors
keywords: 5-AZA-dc; 5-aza-2-deoxycytidine; EMT; GAPDH; KLF4; Krüppel-like factor 4; NMIBC; PCR; RFS; TURBT; carcinoma; epithelial-to-mesenchymal transition; genes; glyceraldehyde-3-phosphate dehydrogenase; mortality; nonmuscle invasive bladder cancer; polymerase chain reaction; recurrence-free survival; transurethral resection of bladder tumor; tumor suppressor; urinary bladder; urothelium