Hu Zhenzhen, Dong Na, Lu Dian, Jiang Xiuqin, Xu Jinjin, Wu Zhiwei, Zheng Datong, Wechsler Daniel S
Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China.
The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu 210011, China; Children's Health Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China.
Cell Signal. 2017 Feb;31:79-86. doi: 10.1016/j.cellsig.2017.01.007. Epub 2017 Jan 6.
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 Mxi1-0. Furthermore, PI3K/AKT/HIF-1α signaling pathway is involved in ROS-mediated Mxi1-0 and VEGF expression in hypoxic HepG2 cells. Finally, Mxi1-0 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 Mxi1-0 via activation of PI3K/AKT/HIF-1α 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.
缺氧诱导的VEGF表达在促进肿瘤血管生成中起关键作用。然而，缺氧条件下调节VEGF表达的分子机制仍知之甚少。在本研究中，我们发现缺氧的HepG2细胞中VEGF的诱导是依赖ROS的。ROS通过上调Mxi1-0介导缺氧诱导的VEGF。此外，PI3K/AKT/HIF-1α信号通路参与缺氧的HepG2细胞中ROS介导的Mxi1-0和VEGF表达。最后，Mxi1-0可反过来调节缺氧的HepG2细胞中的ROS生成，形成一个正反馈环。综上所述，本研究证明了一个正调控反馈环，其中ROS通过激活PI3K/AKT/HIF-1α途径介导缺氧诱导的Mxi1-0，这些事件反过来又提高ROS生成并促进缺氧诱导的VEGF表达。这些发现可为基于抑制肝细胞癌（HCC）血管生成设计新疗法提供理论依据。
