The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer.
BACKGROUND
MiR-214 is aberrantly regulated in several tumours, but its underlying mechanisms in colorectal cancer (CRC) metastasis remain largely unknown. This study aimed to demonstrate the function and potential mechanism of miR-214 in regulating invasion and metastasis of CRC.


METHODS
The transcription factor and targets of miR-214 were predicted by bioinformatics and validated using ChIP and dual-luciferase reporter assay. DNA methylation status was explored using bisulphite sequencing PCR. The in vitro and in vivo function of miR-214 in CRC was evaluated using MTT, plate colony formation, Matrigel invasion and animal models. Real-time PCR or western blotting was performed to detect FOXD3, miR-214 and MED19 expressions in CRC cells and clinical specimens.


RESULTS
MiR-214 was downregulated in CRC and was significantly correlated with lymphatic metastasis. Downregulation of miR-214 might due to promoter hypermethylation in CRC. FOXD3 was validated as a transcription factor of miR-214 by ChIP assay. Dual-luciferase assay identified MED19 as a target of miR-214 in CRC. In vitro and in vivo experiments showed that miR-214 mediated the inhibiting effect of FOXD3 on proliferation, invasion and metastasis by targeting MED19. Spearman's correlation analysis showed a positive correlation between FOXD3 and miR-214, and negative correlations between FOXD3 and MED19, miR-214 and MED19 in CRC cells and clinical specimens.


CONCLUSIONS
FOXD3/miR-214/MED19 axis is important for the regulation of growth, invasion and metastasis of CRC. Targeting the miR-214-mediated axis might be helpful for the treatment of CRC.
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Department of Pathology, Xinxiang Medical University, Xinxiang city 453003, Henan Province, China.
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GY
He
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou city 510515, Guangdong Province, China.
J L
JL
Hu
First School of Clinical Medicine, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.
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Zhou
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou city 510515, Guangdong Province, China.
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XH
Zhu
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou city 510515, Guangdong Province, China.
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SN
Xin
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou city 510515, Guangdong Province, China.
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Zhang
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou city 510515, Guangdong Province, China.
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GF
Lu
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou city 510515, Guangdong Province, China.
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Liao
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou city 510515, Guangdong Province, China.
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YQ
Ding
Department of Pathology, Southern Medical University, Guangzhou city 510515, Guangdong Province, China.|Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou city 510515, Guangdong Province, China.
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Liang
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation; D017931:DNA Primers; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D056892:Mediator Complex / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*
D017931:DNA Primers; C503514:FOXD3 protein, human; D051858:Forkhead Transcription Factors; C558319:MED19 protein, human; C547397:MIRN214 microRNA, human; D056892:Mediator Complex; D035683:MicroRNAs