MicroRNA-20a-5p promotes colorectal cancer invasion and metastasis by downregulating Smad4
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Dantong Cheng1,*, Senlin Zhao1,5,*, Huamei Tang2,*, Dongyuan Zhang1, Hongcheng Sun1, Fudong Yu1, Weiliang Jiang4,*, Ben Yue1, Jingtao Wang1, Meng Zhang3, Yang Yu1, Xisheng Liu1, Xiaofeng Sun5, Zongguang Zhou6, Xuebin Qin7, Xin Zhang8, Dongwang Yan1, Yugang Wen1,5, Zhihai Peng1
1Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
2Department of Pathology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
3Department of Pathology, Fudan University Affiliated Shanghai Cancer Center, Shanghai, China
4Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
5Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
6Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
7Department of Neuroscience, School of Medicine, Temple University, Philadelphia, PA, USA
8Department of Pathology, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, China
*These authors contributed equally to this work
Zhihai Peng, email: [email protected]
Yugang Wen, email: [email protected]
Dongwang Yan, email: [email protected]
Keywords: miR-20a-5p, colorectal cancer, metastasis, prognosis, Smad4
Received: February 09, 2016 Accepted: May 28, 2016 Published: June 07, 2016
Background: Tumor metastasis is one of the leading causes of poor prognosis for colorectal cancer (CRC) patients. Loss of Smad4 contributes to aggression process in many human cancers. However, the underlying precise mechanism of aberrant Smad4 expression in CRC development is still little known.
Results: miR-20a-5p negatively regulated Smad4 by directly targeting its 3′UTR in human colorectal cancer cells. miR-20a-5p not only promoted CRC cells aggression capacity in vitro and liver metastasis in vivo, but also promoted the epithelial-to-mesenchymal transition process by downregulating Smad4 expression. In addition, tissue microarray analysis obtained from 544 CRC patients’ clinical characters showed that miR-20a-5p was upregulated in human CRC tissues, especially in the tissues with metastasis. High level of miR-20a-5p predicted poor prognosis in CRC patients.
Methods: Five miRNA target prediction programs were applied to identify potential miRNA(s) that target(s) Smad4 in CRC. Luciferase reporter assay and transfection technique were used to validate the correlation between miR-20a-5p and Smad4 in CRC. Wound healing, transwell and tumorigenesis assays were used to explore the function of miR-20a-5p and Smad4 in CRC progression in vitro and in vivo. The association between miR-20a-5p expression and the prognosis of CRC patients was evaluated by Kaplan–Meier analysis and multivariate cox proportional hazard analyses based on tissue microarray data.
Conclusions: miR-20a-5p, as an onco-miRNA, promoted the invasion and metastasis ability by suppressing Smad4 expression in CRC cells, and high miR-20a-5p predicted poor prognosis for CRC patients, providing a novel and promising therapeutic target in human colorectal cancer.
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