title: A positive feedback loop between ROS and Mxi1-0 promotes hypoxia-induced VEGF expression in human hepatocellular carcinoma cells.
abstract: 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.
authors.affiliation: Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Na
authors.initials: N
authors.lastname: Dong
authors.affiliation: The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu 210011, China.
authors.forename: Dian
authors.initials: D
authors.lastname: Lu
authors.affiliation: Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China.
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Center for Public Health Research, Medical School, Nanjing, Jiangsu 210093, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wu
authors.affiliation: 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. Electronic address: dtzheng@njmu.edu.cn.
authors.forename: Datong
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wechsler
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D025461:Feedback, Physiological; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C079440:MXI1 protein, human
keywords: Hepatocellular carcinoma; Hypoxia; Mxi1-0; ROS; VEGF