miR-551b regulates epithelial-mesenchymal transition and metastasis of gastric cancer by inhibiting ERBB4 expression
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Guangyuan Song1,*, Hongcheng Zhang1,*, Chenlin Chen1, Lijie Gong1, Biao Chen1, Shaoyun Zhao1, Ji Shi2, Ji Xu3,4 and Zaiyuan Ye3,4
1The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
2The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
3Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, China
4Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, Zhejiang, China
*These authors contributed equally to this work and are co-first authors.
Ji Xu, email: [email protected]
Zaiyuan Ye, email: [email protected]
Keywords: miR-551b, epithelial-mesenchymal transition (EMT), metastasis, gastric cancer, ERBB4
Received: December 05, 2016 Accepted: April 02, 2017 Published: April 24, 2017
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.
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