Wang Duoduo, Weng Qinjie, Zhang Lei, He Qiaojun, Yang Bo
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 388# Yuhangtang Road, Hangzhou, 310058, China.
Cell Mol Neurobiol. 2009 May;29(3):391-401. doi: 10.1007/s10571-008-9331-9. Epub 2008 Dec 2.
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.
据报道，肿瘤缺氧在许多肿瘤部位都是一个负面的预后因素，这表明肿瘤缺氧与转移效率增加之间存在正相关。证据表明，血管内皮生长因子（VEGF）在肿瘤生长中刺激血管生成，并介导神经保护以防止凋亡性细胞死亡。将人神经母细胞瘤细胞（CHP126）暴露于中度缺氧环境中不同时间，以探索分子应激反应。在暴露早期观察到凋亡特征，如Bax/Bcl-2比值增加和caspase 3激活，但随着缺氧处理时间的延长，这些效应被逆转。缺氧还以时间相关的方式激活了MAPKs信号通路，这些通路参与了CHP126细胞缺氧相关抗性的调节。同时，发现VEGF及其受体KDR除了缺氧效应外，还与MAPKs信号通路相互作用。此外，利用重组人血管内皮生长因子（rhVEGF(165)）来识别VEGF增加了Bcl-2和procaspase 3的表达，通过相互作用在缺氧状态下促成血管生成反应与Bcl-2的协同关系，而ERK MAPK的激活对两者的产生都很重要。这些改变的信号可能对预测不良预后至关重要；因此，我们的研究为肿瘤细胞的凋亡和血管生成控制提供了新的见解，并提出了一种基于在神经母细胞瘤缺氧状态下阻断缺氧诱导的VEGF信号传导的策略。
