期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 49, 期 6, 页码 1072-1081出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.06.023
关键词
Bladder cancer; BLT2; Invasion; Metastasis; Reactive oxygen species; Free radicals
资金
- Ministry of Education, Science, and Technology, Korea
- KICOS [K20704000007-09A0500-00710]
Aggressive bladder cancer is a major cause of morbidity and mortality. Despite the fact that metastatic disease results in death in the majority of bladder cancer cases, the molecular events regulating the invasive phenotype of aggressive bladder cancer are not well understood. In this study, immunohistochemical examination showed that the leukotriene B-4 receptor BLT2 is overexpressed in advanced malignant bladder cancers (human transitional cell carcinomas) in proportion to advancing stages, with high prognostic significance (p<0.001). Blockade of BLT2 with the specific antagonist LY255283 or siRNA knockdown significantly suppressed the invasiveness of highly aggressive 253 J-BV bladder cancer cells. Moreover, our results demonstrated that BLT2 mediates invasiveness through a signaling pathway dependent on NAD(P)H oxidase (Nox) 1- and Nox4-induced generation of reactive oxygen species (ROS) and subsequent NF-kappa B stimulation. Metastasis of 253 J-BV cells in mice was also dramatically suppressed by inhibition of BLT2 or its signaling. These findings suggest that a BLT2-Nox-ROS-NF-kappa B cascade plays a critical role in bladder cancer invasion and metastasis. (C) 2010 Elsevier Inc. All rights reserved.
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