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Gastric Epithelial Reactive Oxygen Species Prevent Normoxic Degradation of Hypoxia-inducible Factor-1α in Gastric Cancer Cells

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Authors
Park, Jung-Hyun; Kim, Tae You; Jong, Hyun-Soon; Kim, Tai Young; Chun, Yang-Sook; Park, Jong-Wan; Lee, Choon-Taek; Jung, Hyun Chae; Kim, Noe Kyeong; Bang, Yung-Jue
Issue Date
2003-01
Citation
Clinical Cancer Research, Vol.9 No.1, pp.433-440
Abstract
The expression of hypoxia inducible factor (HIF)-1alpha protein is tightly regulated by cellular oxygen status. Namely, HIF-1alpha protein is degraded rapidly in normoxic cells, whereas hypoxia stabilizes HIF-1alpha to transactivate hypoxia-responsive genes. Here we show that HIF-1alpha protein is expressed aberrantly in gastric cancer cells under normoxia in a reactive oxygen species (ROS)-dependent manner. The normoxic expression of HIF-1alpha in concordance with its DNA binding activity enhances the transcription of target genes such as vascular endothelial growth factor. The aberrant normoxic expression of HIF-1alpha is not associated with genetic abnormalities such as the loss of von Hippel-Lindau tumor suppressor, but is well correlated with endogenous ROS (hydrogen peroxide) generation. HIF-1alpha expression is blocked by nonmitochondrial ROS inhibitors, but not by inhibitors of mitochondrial electron transfer, which indicates that nonmitochondrial ROS stabilize HIF-1alpha protein in these cells. Gastric epithelial ROS have been linked to Helicobacter pylori-induced gastric carcinogenesis. This study demonstrates for the first time that ROS from H. pylori-infected gastric epithelial cells induce HIF-1alpha expression and subsequently activate HIF-1alpha-mediated transcription. Taken together, these results provide a novel mechanism of HIF-1alpha stabilization in gastric cancer, and demonstrate that gastric epithelial ROS, endogenously generated or H. pylori-stimulated, lead to the constant expression of HIF-1alpha protein under normoxia.
ISSN
1078-0432
URI
https://hdl.handle.net/10371/173044
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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