MiR-373 targeting of the Rab22a oncogene suppresses tumor invasion and metastasis in ovarian cancer

// Yue Zhang 1, * , Fu-Jun Zhao 2, * , Li-Lan Chen 1 , Luo-Qiao Wang 1 , Kenneth P. Nephew 3 , Ying-Li Wu 4 , Shu Zhang 1 1 Department of Obstetrics and Gynecology, RenJi Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China 2 Department of Urology, Shanghai First People’s Hospital, Shanghai Jiao-Tong University, Shanghai, 200080, China 3 Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA 4 Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China * These authors contributed eqully to this work Correspondence to: Shu Zhang, e-mail: drzhangshu@126.com Ying-Li Wu, e-mail: wuyingli@shsmu.edu.cn Keywords: ovarian cancer, miR-373, Rab22a, invasion, metastasis Received: July 19, 2014      Accepted: October 06, 2014      Published: November 07, 2014 ABSTRACT Metastasis is major cause of mortality in patients with ovarian cancer. MiR-373 has been shown to play pivotal roles in tumorigenesis and metastasis; however, a role for miR-373 in ovarian cancer has not been investigated. In this study, we show that the miR-373 expression is down-regulated in human epithelial ovarian cancer (EOC) and inversely correlated with clinical stage and histological grade. Ectopic overexpression of miR-373 in human EOC cells suppressed cell invasion in vitro and metastasis in vivo , and the epithelial–mesenchymal transition process. Silencing the expression of miR-373 resulted in an increased migration and invasion of EOC cells. Using integrated bioinformatics analysis, gene expression arrays, and luciferase assay, we identified Rab22a as a direct and functional target of miR-373 in EOC cells. Expression levels of miR-373 were inversely correlated with Rab22a protein levels in human EOC tissues. Rab22a knockdown inhibited invasion and migration of EOC cells, increased E-cadherin expression, and suppressed the expression of N-cadherin. Moreover, overexpression of Rab22a abrogated miR-373-induced invasion and migration of EOC cells. Taken together, these results demonstrate that miR-373 suppresses EOC invasion and metastasis by directly targeting Rab22a gene, a new potential therapeutic target in EOC.