Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1α in neuroblastoma cells
Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1α in neuroblastoma cells
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DOI：
10.1158/0008-5472.can-05-2789
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发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Thiele, CJ
中科院分区：
文献类型：
--
作者：
Nakamura, K;Martin, KC;Thiele, CJ
血管生成和/或血管内皮生长因子（VEGF）在神经母细胞瘤肿瘤中的表达程度与转移、N-myc扩增和不良临床结果相关。最近，我们发现胰岛素样生长因子-1和血清源性生长因子通过诱导缺氧诱导因子-1 α (HIF-1 α)刺激神经母细胞瘤细胞中VEGF的表达。由于神经母细胞瘤肿瘤预后不良的另一个标志是脑源性神经营养因子（BDNF）及其酪氨酸激酶受体TrkB的高表达，因此我们试图评估BDNF和TrkB在VEGF表达调节中的作用。在无血清培养基中培养的神经母细胞瘤细胞中，BDNF作用8 ~ 16小时后VEGF mRNA水平升高。BDNF诱导VEGF和HIF-1 α蛋白增加，而HIF-1 β水平不受影响。BDNF诱导VEGF启动子活性增加2- 4倍，如果VEGF启动子中的缺氧反应元件发生突变，则可以消除这种活性。转染HIF-1 α小干扰RNA阻断bdnf刺激的VEGF启动子活性和VEGF蛋白表达的增加。bdnf刺激的HIF-1 α和VEGF表达的增加需要TrkB酪氨酸激酶活性，并被磷脂酰肌醇3-激酶（PI3K）和哺乳动物雷帕霉素靶蛋白（mTOR）途径的抑制剂完全阻断。这些数据表明，BDNF在神经母细胞瘤细胞中发挥调节VEGF水平的作用，针对BDNF/TrkB、PI3K、mTOR信号转导通路和/或HIF-1 α的靶向治疗具有抑制VEGF表达和限制神经母细胞瘤肿瘤生长的潜力。
The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Recently, we have shown that insulin-like growth factor-I and serum-derived growth factors stimulate VEGF expression in neuroblastoma cells via induction of hypoxia-inducible factor-1 alpha (HIF-1 alpha). Because another marker of poor prognosis in neuroblastoma tumors is high expression of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, TrkB, we sought to evaluate the involvement of BDNF and TrkB in the regulation of VEGF expression. VEGF mRNA levels in neuroblastoma cells cultured in serum-free media increased after 8 to 16 hours in BDNF. BDNF induced increases in VEGF and HIF-1 alpha protein, whereas HIF-1 beta levels were unaffected. BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated. Transfection of HIF-1 alpha small interfering RNA blocked BDNF-stimulated increases in VEGF promoter activity and VEGF protein expression. The BDNF-stimulated increases in HIF-1 alpha and VEGF expression required TrkB tyrosine kinase activity and were completely blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1 alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.