ROS enhance angiogenic properties via regulation of NRF2 in tumor endothelial cells

Oncotarget
Takayuki HojoKyoko Hida

Abstract

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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Citations

May 24, 2019·Free Radical Research·David L NewmanStephen L Gregory
Aug 21, 2019·International Journal of Molecular Sciences·Mirco GalièManuela Malatesta
Aug 21, 2019·Cell & Bioscience·Bahareh KardidehKamran Mansouri
May 24, 2019·Cell Communication and Signaling : CCS·Dongsheng YuanTieliu Shi
Oct 12, 2019·Cancers·Nako MaishiKyoko Hida
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Aug 2, 2019·Toxicology Research·Yan SunShuangxi He
Sep 18, 2020·International Journal of Pharmaceutics·Elaheh MirhadiMahmoud Reza Jaafari
Dec 18, 2020·Frontiers in Chemistry·Raid AlhayazaM Ruhul Abid
Mar 16, 2021·Critical Reviews in Oncology/hematology·RamaRao MallaGanji Purnachandra Nagaraju
Mar 30, 2021·Frontiers in Genetics·Zaheenul Islam SiddiquiSyed Naqui Kazim
Dec 29, 2020·American Journal of Physiology. Cell Physiology·Ting-Yu ChinSheau-Huei Chueh
Apr 11, 2021·FEBS Letters·Jelle VerhoevenPatrizia Agostinis

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Methods Mentioned

BETA
xenografts
PCR
FACS
Protein Assay

Software Mentioned

Image J
Fluoview FV10 - ASM Viewer

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