Gastric epithelial reactive oxygen species prevent normoxic degradation of hypoxia-inducible factor-1alpha in gastric cancer cells.
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.
Park
Jung-Hyun
JH
Department of Tumor Biology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Kim
Tae-You
TY
Jong
Hyun-Soon
HS
Kim
Tai Young
TY
Chun
Yang-Sook
YS
Park
Jong-Wan
JW
Lee
Choon-Taek
CT
Jung
Hyun Chae
HC
Kim
Noe Kyeong
NK
Bang
Yung-Jue
YJ
D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D012313:RNA; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D010100:Oxygen