title: microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis, and angiogenesis of neuroblastoma cells.
abstract: Matrix metalloproteinase (MMP)-14 is the only membrane-anchored MMP that plays a critical role in tumor metastasis and angiogenesis. However, the mechanisms underlying MMP-14 expression in tumors still remain largely unknown. In this study, MMP-14 immunostaining was identified in 29/42 neuroblastoma tissues, which was correlated with clinicopathologic features and shorter patients' survival. In subtotal 20 neuroblastoma cases, microRNA 9 (miR-9) was downregulated and inversely correlated with MMP-14 expression. Bioinformatics analysis revealed a putative miR-9-binding site in the 3'-untranslated region (3'-UTR) of MMP-14 mRNA. Overexpression or knockdown of miR-9 responsively altered both the mRNA and protein levels of MMP-14 and its downstream gene, vascular endothelial growth factor, in cultured neuroblastoma cell lines SH-SY5Y and SK-N-SH. In an MMP-14 3'-UTR luciferase reporter system, miR-9 downregulated the luciferase activity, and these effects were abolished by a mutation in the putative miR-9-binding site. Overexpression of miR-9 suppressed the invasion, metastasis, and angiogenesis of SH-SY5Y and SK-N-SH cells in vitro and in vivo. In addition, the effects of miR-9 on MMP-14 expression, adhesion, migration, invasion, and angiogenesis were rescued by overexpression of MMP-14 in these cells. Furthermore, anti-miR-9 inhibitor or knockdown of MMP-14 respectively increased or inhibited the migration, invasion, and angiogenesis of neuroblastoma cells. These data indicate that miR-9 suppresses MMP-14 expression via the binding site in the 3'-UTR, thus inhibiting the invasion, metastasis, and angiogenesis of neuroblastoma.
authors.affiliation: Department of Pediatric Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Meng
authors.initials: M
authors.lastname: Qi
authors.forename: Shiwang
authors.initials: S
authors.lastname: Li
authors.forename: Teng
authors.initials: T
authors.lastname: Qi
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Liduan
authors.initials: L
authors.lastname: Zheng
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D020868:Gene Silencing; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012323:RNA Processing, Post-Transcriptional
chemical_list: D020413:3' Untranslated Regions; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D053511:Matrix Metalloproteinase 14