BLT2 promotes the invasion and metastasis of aggressive bladder cancer cells through a reactive oxygen species-linked pathway.
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 253J-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-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.
Kim
Eun-Young
EY
College of Life Sciences and Biotechnology, College of Medicine, Korea University, Seoul 136-701, Korea.
Seo
Ji-Min
JM
Kim
Cheolmin
C
Lee
Jung-Eun
JE
Lee
Kyung-Mi
KM
Kim
Jae-Hong
JH
D000818:Animals; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000556:secondary; D045744:Cell Line, Tumor; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D015533:Transcriptional Activation; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
C485878:LTB4R2 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D007975:Leukotriene B4; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human; C063823:LY 255283