Background 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. Patients and methods 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. Results 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. Conclusions KLF4 promotes TWIST1-mediated EMT and may represent a novel prognostic predictor in UCB.
|Journal||Urologic Oncology: Seminars and Original Investigations|
|State||Published - 1 Nov 2016|
- Epithelial-mesenchymal transition
- Krüppel-like factor 4
- Urothelial carcinoma of bladder