MicroRNA-20a-5p promotes colorectal cancer invasion and metastasis by downregulating Smad4.
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.
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Dantong
D
Cheng
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Senlin
S
Zhao
Department of Pathology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Huamei
H
Tang
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Dongyuan
D
Zhang
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Hongcheng
H
Sun
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Fudong
F
Yu
Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Weiliang
W
Jiang
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Ben
B
Yue
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Jingtao
J
Wang
Department of Pathology, Fudan University Affiliated Shanghai Cancer Center, Shanghai, China.
Meng
M
Zhang
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Yang
Y
Yu
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Xisheng
X
Liu
Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Xiaofeng
X
Sun
Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Zongguang
Z
Zhou
Department of Neuroscience, School of Medicine, Temple University, Philadelphia, PA, USA.
Xuebin
X
Qin
Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
Xin
X
Zhang
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Dongwang
D
Yan
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Yugang
Y
Wen
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Zhihai
Z
Peng
D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D051901:Smad4 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*
D020413:3' Untranslated Regions; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; C497796:SMAD4 protein, human; D051901:Smad4 Protein
Smad4; colorectal cancer; metastasis; miR-20a-5p; prognosis