miRNA-337-3p suppresses neuroblastoma progression by repressing the transcription of matrix metalloproteinase 14

// Xuan Xiang 1, * , Hong Mei 1, * , Xiang Zhao 1, * , Jiarui Pu 1 , Dan Li 1 , Hongxia Qu 1 , Wanju Jiao 2 , Jihe Zhao 3 , Kai Huang 4 , Liduan Zheng 2, 4 , Qiangsong Tong 1, 4 1 Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China 2 Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China 3 Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA 4 Clinical 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 Correspondence to: Qiangsong Tong, e-mail: qs_tong@hotmail.com Liduan Zheng, e-mail: ld_zheng@hotmail.com Keywords: neuroblastoma, microRNA-337-3p, matrix metalloproteinase 14, transcriptional repression Received: February 18, 2015      Accepted: June 03, 2015      Published: June 15, 2015 ABSTRACT 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.