Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14.

Matrix metalloproteinase 14 (MMP-14) is the only membrane-anchored MMP that plays critical roles in tumorigenesis and aggressiveness. However, the regulatory mechanisms underlying the high MMP-14 expression in neuroblastoma (NB), a highly malignant tumor in childhood, still remain unclear. Herein, we applied an integrative approach to analyze the public datasets, and identified hepatocyte nuclear factor 4 alpha (HNF4α) as a crucial transcription factor facilitating the MMP-14 expression in NB. In clinical NB tissues, HNF4α was up-regulated and positively correlated with MMP-14 expression, and was an independent prognostic factor for unfavorable outcome of patients. Luciferase reporter and chromatin immunoprecipitation assays indicated that HNF4α directly targeted the binding site within the MMP-14 promoter to facilitate its transcription. Knockdown of HNF4α suppressed the invasion, metastasis and angiogenesis of NB cells in vitro and in vivo. Conversely, ectopic expression of HNF4α promoted the invasion, metastasis and angiogenesis of NB cells. Importantly, restoration of MMP-14 expression prevented the tumor cells from HNF4α-mediated changes in these biological features. Taken together, HNF4α exhibits oncogenic activity that affects the aggressiveness and angiogenesis of NB through activating the transcription of MMP-14.

Xiang X ，Zhao X ，Qu H ，Li D ，Yang D ，Pu J ，Mei H ，Zhao J ，Huang K ，Zheng L ，Tong Q ... -  《-》

Intelectin 1 suppresses the growth, invasion and metastasis of neuroblastoma cells through up-regulation of N-myc downstream regulated gene 2.

Li D ，Mei H ，Pu J ，Xiang X ，Zhao X ，Qu H ，Huang K ，Zheng L ，Tong Q ... -  《Molecular Cancer》

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

Xiang X ，Mei H ，Zhao X ，Pu J ，Li D ，Qu H ，Jiao W ，Zhao J ，Huang K ，Zheng L ，Tong Q ... -  《Oncotarget》

Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.

Qu H ，Zheng L ，Jiao W ，Mei H ，Li D ，Song H ，Fang E ，Wang X ，Li S ，Huang K ，Tong Q ... -  《Scientific Reports》

microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis, and angiogenesis of neuroblastoma cells.

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.

Zhang H ，Qi M ，Li S ，Qi T ，Mei H ，Huang K ，Zheng L ，Tong Q ... -  《-》