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 the present study, immunohistochemical examination showed that the leukotriene B(4) receptor BLT2 is overexpressed in advanced malignant bladder cancers [human transitional cell carcinomas (TCCs)] 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 253J-BV bladder cancer cells. Moreover, our results demonstrated that BLT2 mediates invasiveness through a signaling pathway dependent on NAD(P)H oxidase-1 and -4 (Nox1/4)-induced generation of reactive oxygen species (ROS) and subsequent NF-kappaB stimulation. Metastasis of 253J-BV cells in mice was also dramatically suppressed by inhibition of BLT2 or its signaling. These findings suggest that a "BLT2-Nox-ROS-NF-kappaB" cascade plays a critical role in bladder cancer invasion and metastasis. Copyright © 2010. Published by Elsevier Inc.

PMID: 20600831 [PubMed - as supplied by publisher] Source: National Library of Medicine.