title: Implications of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 signaling in human neuroblastoma progression.
abstract: OBJECTIVE
  Neuroblastoma is a common pediatric tumor that is derived from improperly differentiated neural crest cells (NCC). We recently revealed that endocrine gland-derived vascular endothelial growth factor/prokineticin-1 (EG-VEGF/Prok-1) is a key factor mediating the growth and differentiation of enteric NCCs during development. In this report, we further elucidate its role in neuroblastoma progression.
  
  
  METHODS
  We studied the expression and copy number of EG-VEGF/Prok-1 receptors (PK-R1 and PK-R2) in 26 neuroblastoma tumors by real-time reverse transcription-PCR and immunohistochemical analysis. Implication of EG-VEGF/Prok-1 signaling in neuroblastoma progression was further shown in a neuroblastoma cell line (SK-N-SH).
  
  
  RESULTS
  We found that all neuroblastoma samples from stages II to IV expressed both PK-R1 and PK-R2. Kruskall-Wallis signed rank tests revealed that the expression level of PK-R1 transcript is associated with the stages and metastasis of the neuroblastoma (P<0.05), and PK-R2 is persistently higher in advanced-stage neuroblastoma samples. About 38% of the neuroblastoma tumors (10:26) possessed MYCN amplification, whereas no PK-R1 and PK-R2 amplifications were detected, suggesting that the overexpression of the receptors was not due to gene amplification. Subsequent functional studies showed that EG-VEGF/Prok-1 activates the Akt pathway to induce the proliferation of neuroblastoma cells. Targeted down-regulation studies revealed that EG-VEGF/Prok-1-mediated proliferation requires the presence of these two receptors, and that PK-R2 is essential for inhibiting apoptosis. In vitro migration and invasion assays also indicated that EG-VEGF/Prok-1 significantly enhances the cell migration/invasion of SK-N-SH.
  
  
  CONCLUSIONS
  Our study has shown for the first time that aberrant EG-VEGF/Prok-1 signaling favors neuroblastoma progression and could be a potential target for future neuroblastoma treatment.
authors.affiliation: Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong, SAR, China, and Department of Pediatric Surgery, The Second Affiliated Hospital of China Medical University, Shenyang, China. engan@hkucc.hku.hk
authors.forename: Elly S W
authors.initials: ES
authors.lastname: Ngan
authors.forename: Francesco Y L
authors.initials: FY
authors.lastname: Sit
authors.forename: KingLiu
authors.initials: K
authors.lastname: Lee
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Yuan
authors.forename: Weilin
authors.initials: W
authors.lastname: Wang
authors.forename: John M
authors.initials: JM
authors.lastname: Nicholls
authors.forename: Kenneth K Y
authors.initials: KK
authors.lastname: Wong
authors.forename: Mercè
authors.initials: M
authors.lastname: Garcia-Barcelo
authors.forename: Vincent C H
authors.initials: VC
authors.lastname: Lui
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004702:Endocrine Glands / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000378:metabolism*
chemical_list: D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived