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Implications of Endocrine Gland–Derived Vascular Endothelial Growth Factor/Prokineticin-1 Signaling in Human Neuroblastoma Progression

Authors' Affiliations: Departments of ¹ Surgery and ² Pathology, University of Hong Kong, Pokfulam, Hong Kong, SAR, China and ³ Department of Pediatric Surgery, The Second Affiliated Hospital of China Medical University, Shenyang, China

Requests for reprints: Elly S.W. Ngan, Department of Surgery, Faculty of Medicine Building, University of Hong Kong, Pokfulam, 21 Sassoon Road, Hong Kong, SAR, China. Phone: 852-2819-9631; Fax: 852-2816-9621; E-mail: engan{at}hkucc.hku.hk; or Paul K.H. Tam, Department of Surgery, University of Hong Kong, Pokfulam, K15, Queen Mary Hospital, Hong Kong, SAR, China. Phone: 852-2855-4850; Fax: 852-2817-3155; E-mail: paultam{at}hkucc.hku.hk.

Purpose: 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.

Experimental Design: 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.

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