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MicroRNA-20a-5p promotes colorectal cancer invasion and metastasis by downregulating Smad4

Dantong Cheng, Senlin Zhao, Huamei Tang, Dongyuan Zhang, Hongcheng Sun, Fudong Yu, Weiliang Jiang, Ben Yue, Jingtao Wang, Meng Zhang, Yang Yu, Xisheng Liu, Xiaofeng Sun, Zongguang Zhou, Xuebin Qin, Xin Zhang, Dongwang Yan, Yugang Wen and Zhihai Peng _

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Oncotarget. 2016; 7:45199-45213. https://doi.org/10.18632/oncotarget.9900

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Abstract

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

Correspondence to:

Zhihai Peng, email: pengpzhh@hotmail.com

Yugang Wen, email: wenyg1502@hotmail.com

Dongwang Yan, email: yandw70@163.com

Keywords: miR-20a-5p, colorectal cancer, metastasis, prognosis, Smad4

Received: February 09, 2016     Accepted: May 28, 2016     Published: June 07, 2016

ABSTRACT

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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