miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

作者：Xuanyu Chen, Xuegang Wang, Anming Ruan, Weiwei Han, Yan Zhao, Xing Lü, Pei Xiao, Hangchuan Shi, Rong Wang, Li Chen, Shaoyong Chen, Quansheng Du, Hongmei Yang, Xiaoping Zhang · 发表于：Clinical Cancer Research · 年份：2014 · DOI：10.1158/1078-0432.ccr-13-3224 · 被引用次数：144 · 研究领域：Axon Guidance and Neuronal Signaling、MicroRNA in disease regulation、Hippo pathway signaling and YAP/TAZ

PURPOSE: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis. EXPERIMENTAL DESIGN: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. RESULTS: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, ...