Epigenetic Inactivation of KLF4 is Associated with Urothelial Cancer Progression and Early Recurrence
Epigenetic Inactivation of KLF4 is Associated with Urothelial Cancer Progression and Early Recurrence
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KLF4 表观遗传失活与尿路上皮癌进展和早期复发相关
DOI：
10.1016/j.juro.2013.08.087
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发表时间：
2014-02-01
影响因子：
6.6
通讯作者：
Xu, Hua
中科院分区：
文献类型：
--
作者：
Li, Heng;Wang, Ji;Xu, Hua
目的：KLF 4是一种在不同恶性肿瘤中具有不同功能的转录因子。材料和方法：采用免疫组化和Sequenom（TM）MassARRAY（R）方法检测KLF 4在尿路上皮癌组织中的表达和启动子区甲基化情况，并分析其与尿路上皮癌的临床相关性和生物学功能。采用Kaplan-Meier法、考克斯回归分析和ROC曲线分析无复发生存率与KLF 4或KLF 4甲基化水平降低的关系。结果：KLF 4基因在尿路上皮癌中表达下调，其机制与启动子甲基化有关。每一个都与非肌层浸润性膀胱癌患者经尿道膀胱癌切除术后的无复发生存率相关，这使它们成为早期复发的有价值的预测生物标志物。此外，在体内和体外实验表明，KLF 4抑制尿路上皮癌细胞的生长，迁移和侵袭抑制上皮间质transition.Conclusions：KLF 4可能是一个抑癌基因在尿路上皮癌，因为下调KLF 4启动子甲基化，将促进癌症的进展。此外，KLF 4表达降低或其启动子高甲基化可能对非肌层浸润性膀胱癌患者的早期复发具有预测价值。
Purpose: 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.Materials and Methods: Immunohistochemistry and Sequenom (TM) MassARRAY (R) 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.