title: FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma.
abstract: The transcription factor forkhead box D3 (FOXD3) plays a crucial role in the development of neural crest cells. However, the function and underlying mechanisms of FOXD3 in the progression of neuroblastoma (NB), an embryonal tumor that is derived from the neural crest, still remain largely unknown. Here, we report that FOXD3 is an important oncosuppressor of NB tumorigenicity and aggressiveness. We found that FOXD3 was down-regulated in NB tissues and cell lines. Patients with high FOXD3 expression have greater survival probability. Over-expression or knockdown of FOXD3 responsively altered both the protein and mRNA levels of N-myc downstream regulated 1 (NDRG1) and its downstream genes, vascular endothelial growth factor and matrix metalloproteinase 9, in cultured NB cell lines SH-SY5Y and SK-N-SH. Luciferase reporter and chromatin immunoprecipitation assays indicated that FOXD3 directly targeted the binding site within NDRG1 promoter to facilitate its transcription. Ectopic expression of FOXD3 suppressed the growth, invasion, metastasis and angiogenesis of SH-SY5Y and SK-N-SH cells in vitro and in vivo. Conversely, knockdown of FOXD3 promoted the growth, migration, invasion and angiogenesis of NB cells. In addition, rescue experiments in FOXD3 over-expressed or silenced NB cells showed that restoration of NDRG1 expression prevented the tumor cells from FOXD3-mediated changes in these biological features. Our results indicate that FOXD3 exhibits tumor suppressive activity that affects the growth, aggressiveness and angiogenesis of NB through transcriptional regulation of NDRG1.
authors.affiliation: Department of Pediatric Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.forename: Meng
authors.initials: M
authors.lastname: Qi
authors.forename: Dehua
authors.initials: D
authors.lastname: Yang
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhao
authors.forename: Xuan
authors.initials: X
authors.lastname: Xiang
authors.forename: Jiarui
authors.initials: J
authors.lastname: Pu
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Liduan
authors.initials: L
authors.lastname: Zheng
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
mesh_terms: D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C503514:FOXD3 protein, human