DNMT1-dependent suppression of microRNA424 regulates tumor progression in human bladder cancer

// Chun-Te Wu 1,2 , Wei-Yu Lin 2,3 , Ying-Hsu Chang 2,4 , Paul-Yang Lin 2,5 , Wen-Cheng Chen 2,6 and Miao-Fen Chen 2,6 1 Department of Urology, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan 2 Chang Gung University, College of Medicine, Taoyuan City, Taiwan 3 Department of Urology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan 4 Department of Urology, Chang Gung Memorial Hospital at Linko, Taoyuan City, Taiwan 5 Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan 6 Department of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan Correspondence to: Miao-Fen Chen, email: // Keywords : bladder cancer, miR424, DNMT1, EGFR Received : March 16, 2015 Accepted : May 30, 2015 Published : June 10, 2015 Abstract The aim of this study was to examine the role of miRNAs regulation by DNMT1 and its underlying mechanisms in bladder cancer. The choice of target miRNAs was based on the analysis of a TaqMan MicroRNA Panel assay. The role of target miRNA in tumor behavior and the related signaling pathways were assessed using the human bladder cancer cell lines. We also evaluated the predictive power of the target miRNA and its link to DNMT1 from 124 clinical bladder cancer specimens. Our results revealed that the miR-424 level is significantly increased when blocking DNMT1 in bladder cancer cells. From the clinical specimen analysis, the staining of miR-424 was inversely correlated with DNMT1 immunoreactivity. The lack of miR-424 expression was significantly linked to aggressive tumor growth, advanced clinical stage and poor prognosis in bladder cancer. Increased miR-424 suppressed the tumor growth rate and invasion ability determined in vitro and in vivo . Furthermore, the EGFR pathway plays a role in the transmission of the miR-424 signal that regulates cell growth and the epithelial-to-mesenchymal transition. These results highlight a potential role for miR-424 as a molecular predictor and therapeutic target in bladder cancer.