title: Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14.
abstract: 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.
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Dehua
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Pu
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
authors.forename: Jihe
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. Electronic address: ld_zheng@hotmail.com.
authors.forename: Liduan
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. Electronic address: qs_tong@hotmail.com.
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D009447:Neuroblastoma / Q000098:blood supply / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011485:Protein Binding; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D047368:Tumor Burden
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Hepatocyte nuclear factor 4 alpha; Matrix metalloproteinase 14; Neuroblastoma; Transcriptional regulation