Modulation of Gene Expression and Cell Cycle Signaling Pathways in Iressa-treated Urinary Bladder Cancer in Rats
Menée sur des rats, cette étude évalue l'effet chimiopréventif du gefitinib sur la tumorigenèse dans le cancer de la vessie
Eleven bladder tumors from control rats, seven tumors from rats treated with Iressa and seven normal bladder epithelia were profiled using Affymetrix Rat Exon 1.0 ST Arrays. We identified 713 down-regulated and 641 up-regulated genes in comparing bladder tumors vs. normal bladder epithelia. In addition, 178 genes were down-regulated and 96 genes were up-regulated when comparing control tumors vs. Iressa-treated tumors. Two coexpression modules that were significantly correlated with tumor status and treatment status were identified (r = 0.70, P = 2.80 × 10-15 (bladder tumor vs. normal bladder epithelium) and r = 0.63, P = 2.00 × 10-42 (Iressa-treated tumor vs. control tumor), respectively). Both tumor module and treatment module were enriched for genes involved in cell cycle processes. Twenty-four and twenty-one highly connected hub genes likely to be key drivers in cell cycle were identified in the tumor module and treatment module, respectively. Analysis of microRNA genes on the array chips demonstrated that tumor module and treatment module were significantly associated with expression levels of let-7c (r = 0.54, P = 3.70 × 10-8 and r = 0.73, P = 1.50 × 10-65 respectively). These results suggest that let-7c down-regulation and its regulated cell cycle pathway may play an integral role in governing bladder tumor suppression or collaborative oncogenesis and that Iressa exhibits its preventive efficacy on bladder tumorigenesis by up-regulating let-7 and inhibiting the cell cycle. Cell culture study confirmed that the increased expression of Let-7c decreases Iressa-treated bladder tumor cell growth.