Implications of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 signaling in human neuroblastoma progression
Implications of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 signaling in human neuroblastoma progression
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DOI：
10.1158/1078-0432.ccr-06-2176
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发表时间：
2007-02-01
影响因子：
11.5
通讯作者：
Tam, Paul K. H.
中科院分区：
文献类型：
--
作者：
Ngan, Elly S. W.;Sit, Francesco Y. L.;Tam, Paul K. H.
目的：神经母细胞瘤是一种常见的小儿肿瘤，来源于分化不良的神经嵴细胞（NCC）。我们最近发现，内分泌腺源性血管内皮生长因子/促动素-1（EG-VEGF/Prok-1）是一个关键因素，介导的生长和分化的肠道NCC在发展过程中。在这份报告中，我们进一步阐明其在神经母细胞瘤progression.Experimental设计的作用：我们研究了EG-VEGF/Prok-1受体（PK-R1和PK-R2）的表达和拷贝数在26神经母细胞瘤肿瘤实时逆转录-PCR和免疫组化分析。EG-VEGF/Prok-1信号转导在神经母细胞瘤进展中的意义在神经母细胞瘤细胞系（SK-N-SH）中进一步显示。结果：我们发现所有II期至IV期的神经母细胞瘤样品均表达PK-R1和PK-R2。Kruskall-Wallis符号秩和检验显示PK-R1转录本的表达水平与神经母细胞瘤的分期和转移有关（P < 0.05），PK-R2在晚期神经母细胞瘤中的表达持续增高。约38%的神经母细胞瘤（10：26）具有MYCN扩增，而未检测到PK-R1和PK-R2扩增，表明受体的过表达不是由于基因扩增。随后的功能研究表明EG-VEGF/Prok-1激活Akt通路以诱导神经母细胞瘤细胞的增殖。靶向下调研究显示EG-VEGF/Prok-1介导的增殖需要这两种受体的存在，并且PK-R2对于抑制细胞凋亡是必不可少的。在体外迁移和侵袭实验也表明，EG-VEGF/Prok-1显着增强细胞迁移/侵袭SK-N-SH.Conclusions：我们的研究首次表明，异常EG-VEGF/Prok-1信号有利于神经母细胞瘤的进展，并可能是一个潜在的目标，为未来的神经母细胞瘤治疗。
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.