title: miRNA-337-3p suppresses neuroblastoma progression by repressing the transcription of matrix metalloproteinase 14.
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.
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Pu
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Wanju
authors.initials: W
authors.lastname: Jiao
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
authors.forename: Jihe
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.|Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Liduan
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.|Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D018450:Disease Progression; D006367:HeLa Cells; D056945:Hep G2 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D014162:Transfection
chemical_list: D035683:MicroRNAs; C544075:Mirn337 microRNA, human; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: matrix metalloproteinase 14; microRNA-337-3p; neuroblastoma; transcriptional repression