microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis and angiogenesis of neuroblastoma cells
Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints de neuroblastome, cette étude met en évidence un mécanisme par lequel le micro-ARN 9, en régulant l'expression de la métalloprotéase matricielle MMP-14, inhibe les processus invasif et métastatique
Matrix metalloproteinase 14 (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 (NB) tissues, which was correlated with clinicopathological features and shorter patients' survival. In subtotal twenty NB cases, microRNA 9 (miR-9) was down-regulated 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. Over-expression or knockdown of miR-9 responsively altered both the mRNA and protein levels of MMP-14 and its downstream gene, vascular endothelial growth factor (VEGF), in cultured NB cell lines SH-SY5Y and SK-N-SH. In a MMP-14 3′-UTR luciferase reporter system, miR-9 down-regulated the luciferase activity, and these effects were abolished by mutations in the putative miR-9 binding site. Over-expression 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 over-expression 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 NB 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 NB.
http://mct.aacrjournals.org/content/early/2012/05/05/1535-7163.MCT-12-0001.abstract