miR-551b regulates epithelial-mesenchymal transition and metastasis of gastric cancer by inhibiting ERBB4 expression

Abstract

// Guangyuan Song 1, * , Hongcheng Zhang 1, * , Chenlin Chen 1 , Lijie Gong 1 , Biao Chen 1 , Shaoyun Zhao 1 , Ji Shi 2 , Ji Xu 3, 4 and Zaiyuan Ye 3, 4 1 The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China 2 The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China 3 Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, China 4 Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, Zhejiang, China * These authors contributed equally to this work and are co-first authors. Correspondence to: Ji Xu, email: xuji120@163.com Zaiyuan Ye, email: zaiyuanye@163.com Keywords: miR-551b, epithelial-mesenchymal transition (EMT), metastasis, gastric cancer, ERBB4 Received: December 05, 2016     Accepted: April 02, 2017     Published: April 24, 2017 ABSTRACT Epithelial-mesenchymal transition (EMT) is an important biological process that is characteristic of malignant tumor cells with metastatic potential. We investigated the role of miR-551b in EMT and metastasis in gastric cancer (GC). We found that low miR-551b levels were associated with EMT, metastasis and a poor prognosis in GC patients. Further, two GC cell lines, MNK45 and SGC7901, exhibited lower miR-551b levels than the GES normal stomach cell line. Exposing MNK45 and SGC7901 cells to TGF-β1 resulted in cell morphology changes characteristic of EMT, which was confirmed by Western blot analysis demonstrating low E-Cadherin and high N-Cadherin and Vimentin levels. Treatment with miR-551b mimics inhibited these EMT changes as well as Transwell migration and invasiveness. We identified ERBB4 as a potential target of miR-551b based on patient data from the TCGA. ERBB4 was upregulated in GC specimens, and its high expression correlated with a poor prognosis of GC patients. Dual luciferase assays revealed that miR-551b directly inhibited ERBB4 by binding to its 3’UTR. Moreover, treatment with miR-551b mimics or the ERBB4 inhibitor AST-1306 inhibited EMT in the GC cell lines. Finally, nude mice xenografted with GC cancer cell lines expressing miR-551b mimics exhibited smaller tumors and longer survival than mice engrafted with control GC cancer cells. These data indicate that miR-551b inhibits EMT and metastasis in GC by inhibiting ERBB4. miR-551b and ERBB4 are thus potential therapeutic targets for the treatment of GC.