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Gastric Epithelial Reactive Oxygen Species Prevent Normoxic Degradation of Hypoxia-inducible Factor-1 in Gastric Cancer Cells¹

Laboratory of Molecular Carcinogenesis and Experimental Therapeutics, Cancer Research Institute [J-H. P., T-Y. K., H-S. J., T. Y. K., Y-J. B.], Department of Tumor Biology [J-H. P., H-S. J., T. Y. K., Y-J. B.], Department of Internal Medicine [T-Y. K., C-T. L., H. C. J., N. K. K., Y-J. B.], and Department of Pharmacology [Y-S. C., J-W. P.], Seoul National University College of Medicine, Seoul 110-799, Korea

The expression of hypoxia inducible factor (HIF)-1 protein is tightly regulated by cellular oxygen status. Namely, HIF-1 protein is degraded rapidly in normoxic cells, whereas hypoxia stabilizes HIF-1 to transactivate hypoxia-responsive genes. Here we show that HIF-1 protein is expressed aberrantly in gastric cancer cells under normoxia in a reactive oxygen species (ROS)-dependent manner. The normoxic expression of HIF-1 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-1 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-1 expression is blocked by nonmitochondrial ROS inhibitors, but not by inhibitors of mitochondrial electron transfer, which indicates that nonmitochondrial ROS stabilize HIF-1 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-1 expression and subsequently activate HIF-1-mediated transcription. Taken together, these results provide a novel mechanism of HIF-1 stabilization in gastric cancer, and demonstrate that gastric epithelial ROS, endogenously generated or H. pylori-stimulated, lead to the constant expression of HIF-1 protein under normoxia.

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