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 MMP14 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 (HNF4 alpha) as a crucial transcription factor facilitating the MMP-14 expression in NB. In clinical NB tissues, HNF4 alpha 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 HNF4 alpha directly targeted the binding site within the MMP14 promoter to facilitate its transcription. Knockdown of HNF4 alpha suppressed the invasion, metastasis and angiogenesis of NB cells in vitro and in vivo. Conversely, ectopic expression of HNF4 alpha promoted the invasion, metastasis and angiogenesis of NB cells. Importantly, restoration of MMP-14 expression prevented the tumor cells from HNF4 alpha-mediated changes in these biological features. Taken together, HNF4 alpha exhibits oncogenic activity that affects the aggressiveness and angiogenesis of NB through activating the transcription of MMP-14. (C) 2015 Elsevier Ireland Ltd. All rights reserved.