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Prognostic and Functional Significance of Thromboxane Synthase Gene Overexpression in Invasive Bladder Cancer

Departments of ¹ Pathology and Laboratory Medicine, ² Biochemistry and Molecular Biology, ³ Urology, ⁴ Pharmacology and Medicine, and ⁵ Biostatistics, Bioinformatics, and Epidemiology and ⁶ Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina and ⁷ Urology and Nephrology Center, Mansoura University, Mansoura, Egypt

Requests for reprints: Dennis K. Watson, Hollings Cancer Center, Medical University of South Carolina, Room 332, 86 Jonathan Lucas Street, Charleston, SC 29425. Phone: 843-792-3962; Fax: 843-792-3940; E-mail: watsondk{at}musc.edu.

Thromboxane synthase (TXAS) is one of the enzymes downstream from cyclooxygenase-2 and catalyzes the synthesis of thromboxane A₂ (TXA₂). TXAS was among the genes we identified based on its overexpression in invasive bladder tumors. TXAS is overexpressed in common forms of bladder tumors: 69 of 97 (71.1%) transitional cell carcinoma (TCC), 38 of 53 (71.6%) squamous cell carcinoma, and 5 of 11 (45.5%) adenocarcinoma relative to nontumor tissue. Overall, 112 of 161 (69.5%) invasive tumors exhibited elevated expression. Significantly, patients with tumors having >4-fold levels of TXAS expression showed significant statistical evidence of lower overall survival expressed by the estimated hazard ratio of 2.74 with P = 0.009 in Cox's regression analysis. TXAS mRNA expression was found to be an independent prognostic marker for patients with bladder cancer. Treatment of bladder cancer cell lines (T24 and TCC-SUP) with TXAS inhibitors and TXA₂ (TP) receptor antagonists reduced cell growth, migration, and invasion, whereas TP agonists stimulated cell migration and invasion. The positive correlation between elevated TXAS expression and shorter patient survival supports a potential role for TXAS-regulated pathways in tumor invasion and metastases and suggests that modulation of the TXAS pathway may offer a novel therapeutic approach. (Cancer Res 2005; 65(24): 11581-7)

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