Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, USA.
Cancer Prev Res (Phila). 2012 Feb;5(2):248-59. doi: 10.1158/1940-6207.CAPR-10-0363. Epub 2011 Oct 7.
The epidermal growth factor receptor inhibitor Iressa has shown strong preventive efficacy in the N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) model of bladder cancer in the rat. To explore its antitumor mechanism, we implemented a systems biology approach to characterize gene expression and signaling pathways in rat urinary bladder cancers treated with Iressa. Eleven bladder tumors from control rats, seven tumors from rats treated with Iressa, and seven normal bladder epithelia were profiled by the Affymetrix Rat Exon 1.0 ST Arrays. We identified 713 downregulated and 641 upregulated genes in comparing bladder tumors versus normal bladder epithelia. In addition, 178 genes were downregulated and 96 genes were upregulated when comparing control tumors versus 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 showed 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 downregulation 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 upregulating 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. The identified hub genes may also serve as pharmacodynamic or efficacy biomarkers in clinical trials of chemoprevention in human bladder cancer.
表皮生长因子受体抑制剂易瑞沙在大鼠 N-丁基-N-(4-羟丁基)-亚硝胺(OH-BBN)膀胱癌模型中显示出很强的预防效果。为了探索其抗肿瘤机制，我们采用系统生物学方法来描述易瑞沙处理的大鼠膀胱癌中的基因表达和信号通路。11 个来自对照大鼠的膀胱癌、7 个来自易瑞沙处理大鼠的膀胱癌和 7 个正常膀胱上皮组织采用 Affymetrix Rat Exon 1.0 ST Arrays 进行了分析。我们在比较膀胱癌与正常膀胱上皮组织时发现了 713 个下调基因和 641 个上调基因。此外，在比较对照肿瘤与易瑞沙处理肿瘤时，有 178 个基因下调，96 个基因上调。两个与肿瘤状态和治疗状态显著相关的共表达模块被鉴定出来[r = 0.70，P = 2.80 × 10(-15)(膀胱癌 vs. 正常膀胱上皮)和 r = 0.63，P = 2.00 × 10(-42)(易瑞沙处理肿瘤 vs. 对照肿瘤)。肿瘤模块和治疗模块均富集了参与细胞周期过程的基因。在肿瘤模块和治疗模块中分别鉴定出 24 个和 21 个高度连接的核心基因，这些基因可能是细胞周期中的关键驱动因素。对芯片上的 microRNA 基因进行分析表明，肿瘤模块和治疗模块与 let-7c 的表达水平显著相关(r = 0.54，P = 3.70 × 10(-8)和 r = 0.73，P = 1.50 × 10(-65))。这些结果表明，let-7c 的下调及其调控的细胞周期途径可能在控制膀胱癌的抑制或协同致癌中发挥重要作用，易瑞沙通过上调 let-7 和抑制细胞周期来发挥其对膀胱癌发生的预防作用。细胞培养研究证实，let-7c 的表达增加会降低易瑞沙处理的膀胱癌细胞的生长。鉴定出的核心基因也可能作为人类膀胱癌化学预防临床试验中的药效或疗效生物标志物。
