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VEGF and Bcl-2 Interact Via MAPKs Signaling Pathway in the Response to Hypoxia in Neuroblastoma

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Abstract

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, rhVEGF165 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.

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Acknowledgments

The authors thank the grant sponsors. Grant information: This study received financial support from the National Natural Science Foundation (30672484), the Natural Science Foundation of Zhejiang Province (R20512), and Zhejiang Provincial Program for the cultivation of High-level Innovative Health talents.

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  1. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 388# Yuhangtang Road, Hangzhou, 310058, China

    Duoduo Wang, Qinjie Weng, Lei Zhang, Qiaojun He & Bo Yang

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  1. Duoduo Wang
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  2. Qinjie Weng
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  3. Lei Zhang
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Correspondence to Qiaojun He or Bo Yang.

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Wang, D., Weng, Q., Zhang, L. et al. VEGF and Bcl-2 Interact Via MAPKs Signaling Pathway in the Response to Hypoxia in Neuroblastoma. Cell Mol Neurobiol 29, 391–401 (2009). https://doi.org/10.1007/s10571-008-9331-9

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  • DOI: https://doi.org/10.1007/s10571-008-9331-9

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