期刊
ONCOTARGET
卷 8, 期 28, 页码 45484-45495出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.17567
关键词
tumor angiogenesis; tumor endothelial cells; reactive oxygen species; biglycan; nuclear factor erythroid 2-related factor 2
资金
- Ministry of Education, Science, and Culture of Japan [16K2055506]
- Northern Advancement Center for Science & Technology of Hokkaido Japan
- Grants-in-Aid for Scientific Research [16K20554, 17K11116, 16K20555] Funding Source: KAKEN
Reactive oxygen species (ROS) are unstable molecules that activate oxidative stress. Because of the insufficient blood flow in tumors, the tumor microenvironment is often exposed to hypoxic condition and nutrient deprivation, which induces ROS accumulation. We isolated tumor endothelial cells (TECs) and found that they have various abnormalities, although the underlying mechanisms are not fully understood. Here we showed that ROS were accumulated in tumor blood vessels and ROS enhanced TEC migration with upregulation of several angiogenesis related gene expressions. It was also demonstrated that these genes were upregulated by regulation of Nuclear factor erythroid 2-related factor 2 (NRF2). Among these genes, we focused on Biglycan, a small leucine-rich proteoglycan. Inhibition of Toll-like receptors 2 and 4, known BIGLYCAN (BGN) receptors, cancelled the TEC motility stimulated by ROS. ROS inhibited NRF2 expression in TECs but not in NECs, and NRF2 inhibited phosphorylation of SMAD2/3, which activates transcription of BGN. These results indicated that ROS-induced BGN caused the pro-angiogenic phenotype in TECs via NRF2 dysregulation.
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