Oncotarget

Research Papers:

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

Takayuki Hojo, Nako Maishi, Alam Mohammad Towfik, Kosuke Akiyama, Noritaka Ohga, Masanobu Shindoh, Yasuhiro Hida, Kazuyuki Minowa, Toshiaki Fujisawa and Kyoko Hida _

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Oncotarget. 2017; 8:45484-45495. https://doi.org/10.18632/oncotarget.17567

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Abstract

Takayuki Hojo1,2,*, Nako Maishi1,*, Alam Mohammad Towfik1,3, Kosuke Akiyama1, Noritaka Ohga1,4, Masanobu Shindoh5, Yasuhiro Hida6, Kazuyuki Minowa3, Toshiaki Fujisawa2 and Kyoko Hida1

1Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan

2Department of Dental Anesthesiology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan

3Department of Dental Radiology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan

4Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan

5Department of Oral Pathology and Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan

6Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

*These authors contributed equally to this work

Correspondence to:

Kyoko Hida, email: [email protected]

Keywords: tumor angiogenesis, tumor endothelial cells, reactive oxygen species, biglycan, nuclear factor erythroid 2-related factor 2

Received: January 06, 2017     Accepted: April 17, 2017     Published: May 02, 2017

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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