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

• HNF4α is highly expressed and positively correlated with MMP-14 levels in neuroblastoma.
• HNF4α is an independent factor for unfavorable outcome of neuroblastoma patients.
• HNF4α facilitates the transcription of MMP-14 via binding with its promoter in neuroblastoma.
• HNF4α promotes the aggressiveness of neuroblastoma through up-regulating MMP-14.
• HNF4α is a novel therapeutic target for neuroblastoma.

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.