A positive feedback loop between ROS and Mxi1-0 promotes hypoxia-induced VEGF expression in human hepatocellular carcinoma cells

VEGF expression induced by hypoxia plays a critical role in promoting tumor angiogenesis. However, the molecular mechanism that modulates VEGF expression under hypoxia is still poorly understood. In this study, we found that VEGF induction in hypoxic HepG2 cells is ROS-dependent ROS mediates hypoxia-induced VEGF by upregulation of Mxil-0. Furthermore, PI3K/AKT/HIF-l alpha signaling pathway is involved in ROS-mediated Mxil-0 and VEGF expression in hypoxic HepG2 cells. Finally, Mxii-0 could in turn regulate ROS generation in hypoxic HepG2 cells, creating a positive feedback loop. Taken together, this study demonstrate a positive regulatory feedback loop in which ROS mediates hypoxia-induced Mxil-0 via activation of PI3K/AKT/HIF-la pathway, events that in turn elevate ROS generation and promote hypoxia-induced VEGF expression. These findings could provide a rationale for designing new therapies based on inhibition of hepatocellular carcinoma (HCC) angiogenesis. (C) 2017 Elsevier Inc. All rights reserved.