miR-101 targeting ZFX suppresses tumor proliferation and metastasis by regulating the MAPK/Erk and Smad pathways in gallbladder carcinoma
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Run-Fa Bao1,2,*, Yi-Jun Shu1,2,*, Yun-Ping Hu1,2,*, Xu-An Wang1,2, Fei Zhang1,2, Hai-Bin Liang1,2, Yuan-Yuan Ye1,2, Huai-Feng Li1,2, Shan-Shan Xiang1,2, Hao Weng1,2, Yang Cao1,2, Xiang-Song Wu1,2, Mao-Lan Li1,2, Wen-guang Wu1,2, Yi-Jian Zhang1,2, Lin Jiang1,2, Qian Dong1, Ying-Bin Liu1,2
1Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
2Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
*These authors have contributed equally to this work
Qian Dong, e-mail: [email protected]
Ying-Bin Liu, e-mail: [email protected]
Keywords: miR-101, ZFX, EMT, TGF-β, gallbladder carcinoma
Received: November 13, 2015 Accepted: February 23, 2016 Published: March 08, 2016
Gallbladder cancer (GBC), the most common malignancy of the bile duct, is highly aggressive and has an extremely poor prognosis, which is a result of early metastasis. As it is regulated being at multiple levels, the metastatic cascade in GBC is complex. Recent evidence suggests that microRNAs (miRNAs) are involved in cancer metastasis and are promising therapeutic targets. In this study, miR-101 was significantly downregulated in tumor tissues, particularly in metastatic tissues. In GBC patients, low miR-101 expression was correlated with tumor size, tumor invasion, lymph node metastasis, TNM stage, and poor survival. Moreover, miR-101 was an independent prognostic marker for GBC. Additionally, miR-101 inhibited GBC cell proliferation, migration, invasion, and TGF-β-induced epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the gene encoding the zinc finger protein X-linked (ZFX) was identified as a direct target of miR-101. More importantly, miR-101 significantly reduced activation of the MAPK/Erk and Smad signaling pathways, resulting in inhibition of TGF-β-mediated induction of EMT. Altogether, our findings demonstrate a novel mechanism by which miR-101 attenuates the EMT and metastasis in GBC cells and suggest that miR-101 can serve as a potential biomarker and therapeutic target for GBC management.
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