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

Yue Zhang,Fu-Jun Zhao,Kenneth P Nephew,Luo-Qiao Wang,Shu Zhang,Li-Lan Chen,Ying-Li Wu

doi:10.18632/oncotarget.2577

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.

Highlights

Ovarian cancer is the leading cause of cancer deaths from gynecological malignancy in Western countries
To explore the expression and significance of miR-373 in ovarian cancer carcinogenesis, the expression of miR-373 was detected in 30 primary epithelial ovarian cancer (PEOC) samples and 15 benign epithelial ovarian tumor tissues using TaqMan quantitative reverse transcriptionpolymerase chain reaction (RT-PCR) analysis
In addition to PEOC, miR-373 expression was detected in ovarian immortal cell line immortalized nontumorigenic human ovarian surface epithelial (IOSE) and a panel of ovarian cancer cell lines cells (Fig. 1A)

Summary

Introduction

Ovarian cancer is the leading cause of cancer deaths from gynecological malignancy in Western countries. Factors involved in the pathogenesis of ovarian cancer metastasis include metastasis suppressor genes (Nm-23, Kiss-1, KAI1, E-cadherin, BRMS1), epithelial-mesenchymal transition (EMT), tumor microenvironment, chemokines, and anoikis resistance have been identified [2,3,4,5,6,7]. In addition www.impactjournals.com/oncotarget to those signaling molecules and cytokines, recent findings have shown that non-protein-coding RNAs, especially microRNAs (miRNAs) are often deregulated in ovarian cancer and are involved in the tumorigenesis and progression of ovarian cancer [8]. The miRNAs are usually dysregulated and function either as tumor suppressors or oncogenes in the initiation and progression of human carcinomas, including ovarian cancer [9]. Few miRNAs, such as miR-200 family [10, 11], let-7 family [11], miR-21 [12] and miR-214 [13] have been studied for their roles in ovarian cancer carcinogenesis

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