title: miRNA-584-5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase 14.
abstract: Matrix metalloproteinase 14 (MMP-14) is a membrane-anchored MMP crucial for tumorigenesis and aggressiveness, and is highly expressed in neuroblastoma (NB), the most common extracranial solid tumor in childhood. Recent evidence shows the emerging roles of endogenous promoter-targeting microRNAs (miRNAs) in regulating gene transcription. However, the roles of miRNAs in the transcription of MMP-14 still remain largely unknown. In this study, through mining computational algorithm program and Argonaute-chromosome interaction dataset, we identified one binding site of miRNA-584-5p (miR-584-5p) within the MMP-14 promoter. In NB tissues, miR-584-5p was under-expressed and inversely correlated with MMP-14 expression, and was an independent prognostic factor for favorable outcome of patients. miR-584-5p precursor attenuated the expression of MMP-14 in a Dicer-dependent manner, resulting in decreased levels of vascular endothelial growth factor, in cultured NB cell lines. In addition, miR-584-5p suppressed the promoter activity of MMP-14, and mutation of miR-584-5p binding site abolished these effects. Mechanistically, miR-584-5p recruited Argonaute 2 to facilitate the enrichment of enhancer of zeste homolog 2, histone H3 lysine 27 trimethylation, and histone H3 lysine 9 dimethylation on MMP-14 promoter in NB cells, which was abolished by repressing the miR-584-5p-promoter interaction. Gain- and loss-of-function studies demonstrated that miR-584-5p suppressed the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. Moreover, restoration of MMP-14 expression rescued the NB cells from changes in these biological features. Taken together, these results indicate that promoter-targeting miR-584-5p exerts tumor suppressive functions in NB through repressing the transcription of MMP-14.
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR 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, PR 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, PR China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR 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, PR 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, PR China.
authors.forename: Huajie
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China.
authors.forename: Wanju
authors.initials: W
authors.lastname: Jiao
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Pu
authors.affiliation: Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR 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, PR China; Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China. Electronic address: ld_zheng@hotmail.com.
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, PR China; Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China. Electronic address: qs_tong@hotmail.com.
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
keywords: Matrix metalloproteinase 14; Neuroblastoma; Transcriptional repression; microRNA-584-5p