miRNA-337-3p suppresses neuroblastoma progression by repressing the transcription of matrix metalloproteinase 14
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Xuan Xiang1,*, Hong Mei1,*, Xiang Zhao1,*, Jiarui Pu1, Dan Li1, Hongxia Qu1, Wanju Jiao2, Jihe Zhao3, Kai Huang4, Liduan Zheng2,4, Qiangsong Tong1,4
1Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
2Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
3Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA
4Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
*These authors have contributed equally to this work
Qiangsong Tong, e-mail: firstname.lastname@example.org
Liduan Zheng, e-mail: email@example.com
Keywords: neuroblastoma, microRNA-337-3p, matrix metalloproteinase 14, transcriptional repression
Received: February 18, 2015 Accepted: June 03, 2015 Published: June 15, 2015
Recent evidence shows the emerging roles of endogenous microRNAs (miRNAs) in repressing gene transcription. However, the miRNAs inhibiting the transcription of matrix metalloproteinase 14 (MMP-14), a membrane-anchored MMP crucial for the tumorigenesis and aggressiveness, still remain largely unknown. In this study, through mining computational algorithm program and genome-wide Argonaute profiling dataset, we identified one binding site of miRNA-337-3p (miR-337-3p) within the MMP-14 promoter. We demonstrated that miR-337-3p was under-expressed and inversely correlated with MMP-14 expression in clinical specimens and cell lines of neuroblastoma (NB), the most common extracranial solid tumor in childhood. Patients with high miR-337-3p expression had greater survival probability. miR-337-3p suppressed the promoter activity, nascent transcription, and expression of MMP-14, resulting in decreased levels of vascular endothelial growth factor, in cultured NB cell lines. Mechanistically, miR-337-3p recognized its binding site and recruited Argonaute 2 to facilitate the enrichment of repressive epigenetic markers and decrease the binding of RNA polymerase II and specificity protein 1 on the MMP-14 promoter. Gain- and loss-of-function studies demonstrated that miR-337-3p suppressed the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. In addition, restoration of MMP-14 expression rescued the NB cells from changes in these biological features. Taken together, these data indicate that miR-337-3p directly binds the MMP-14 promoter to repress its transcription, thus suppressing the progression of NB.
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