VEGF and Bcl-2 Interact Via MAPKs Signaling Pathway in the Response to Hypoxia in Neuroblastoma
VEGF and Bcl-2 Interact Via MAPKs Signaling Pathway in the Response to Hypoxia in Neuroblastoma
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VEGF 和 Bcl-2 在神经母细胞瘤缺氧反应中通过 MAPKs 信号通路相互作用
DOI：
10.1007/s10571-008-9331-9
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发表时间：
2009-05-01
影响因子：
4
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Wang, Duoduo;Weng, Qinjie;Yang, Bo
据报道，肿瘤缺氧在许多肿瘤部位是一个负面的预后因素，这表明肿瘤缺氧和转移效率增加之间呈正相关。有证据表明，血管内皮生长因子（VEGF）刺激肿瘤生长中的血管生成，并介导神经保护以防止凋亡细胞死亡。以人神经母细胞瘤细胞（CHP 126）为研究对象，研究了不同低氧时间对细胞分子应激反应的影响。缺氧早期可引起Bax/Bcl-2比值升高和caspase-3活化，但随着缺氧时间延长，上述作用逐渐逆转。缺氧还以时间相关的方式激活MAPK信号通路，参与CHP 126细胞缺氧抗性的调节。VEGF及其受体KDR与MAPKs信号通路相互作用，但不受缺氧的影响。此外，利用rhVEGF（165）来辨别VEGF增加Bcl-2和半胱氨酸天冬氨酸蛋白酶原3的表达，通过串扰促进缺氧中血管生成反应与Bcl-2的协同关系，而ERK MAPK的激活对于两种产生都是重要的。这些改变的信号可能是至关重要的预测一个贫穷的结果，因此，我们的知识提供了新的见解肿瘤细胞的凋亡和血管生成的控制，并提出了一个战略的基础上缺氧诱导的VEGF信号在缺氧神经母细胞瘤的封锁。
Tumor hypoxia has been reported to be a negative prognostic factor in a number of tumor sites, which suggests a positive correlation between tumor hypoxia and increased metastatic efficiency. Evidence shows that vascular endothelial growth factor (VEGF) stimulates angiogenesis in tumor growth and mediates neuroprotection to prevent an apoptotic cell death. Human neuroblastoma cells (CHP126) were exposed to moderate hypoxia for different time spans to explore the molecular stress responses. Apoptotic features as an increase of Bax/Bcl-2 ratio and activation of caspase 3 were observed at early period of exposure time, but these effects were reversed with the extension of hypoxic treatment. Hypoxia also activated MAPKs signaling pathways in a time-relative manner, which were involved in the regulation of hypoxia-related resistance of CHP126 cells. Meanwhile, VEGF and its receptor KDR were found to interact with MAPKs signaling pathways except the effect of hypoxia. Furthermore, rhVEGF(165) was utilized to discern that VEGF increased Bcl-2 and procaspase 3 expressions, contributing to a synergistic relationship of an angiogenic response with Bcl-2 in hypoxia via a cross talk, while the activation of ERK MAPK is important for both productions. These altered signals may be critical to predict a poor outcome; therefore, our knowledge provides new insight into apoptosis and angiogenesis control of tumor cells and suggests a strategy based on the blockade of hypoxia-induced VEGF signaling under hypoxia in neuroblastoma.