MicroRNA-31 functions as a tumor suppressor and increases sensitivity to mitomycin-C in urothelial bladder cancer by targeting integrin α5

// Tianyuan Xu 1, * , Liang Qin 1, * , Zhaowei Zhu 2 , Xianjin Wang 1 , Yue Liu 3 , Yong Fan 3 , Shan Zhong 1 , Xiaojing Wang 1 , Xiaohua Zhang 1 , Leilei Xia 1 , Xiang Zhang 1 , Chen Xu 3 , Zhoujun Shen 1 1 Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 2 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China 3 Shanghai Key Laboratory of Reproductive Medicine, School of Medicine, Shanghai Jiaotong University, Shanghai, China * These authors contributed equally to this work Correspondence to: Zhoujun Shen, email: shenzj68@sina.cn Keywords: microRNA-31, integrin α5, bladder cancer, chemotherapy, mitomycin-C Received: January 09, 2016 Accepted: March 16, 2016 Published: March 30, 2016 ABSTRACT Urothelial bladder cancer (UBC) is a common genitourinary malignancy. MiR-31, a well-identified miRNA, exhibits diverse properties in different cancers. However, the specific functions and mechanisms of miR-31 in UBC have not been investigated. In this study, tumor samples, especially invasive UBC, showed significantly reduced level of miR-31, as compared with normal urothelium. Prognostic analysis using the EORTC model showed that down-regulation of miR-31 correlated with higher risks of recurrence and progression in noninvasive UBC cases. Remarkably, overexpression of miR-31 mimics in UBC cell lines inhibited cell proliferation, migration and invasion. Integrin α5 (ITGA5), an integrin family member, was subsequently identified as a direct target of miR-31 in UBC cells. When treated with mitomycin-C (MMC), miR-31-expressing UBC cells displayed lower survival and higher apoptotic rates, and deactivated Akt and ERK. These effects arising from miR-31 overexpression were abrogated by ITGA5 restoration. Furthermore, miR-31 markedly inhibited tumor growth and increased the effectiveness of MMC in UBC xenografts. In summary, our data suggest that miR-31 is a prognostic predictor and can serve as a potential therapeutic target of UBC.