对苯二甲酸促进大鼠膀胱癌发生的细胞周期调节机制研究
Study on Cell Cycle Regulatory Mechanism in Rat Bladder Carcinogenesis Promoted by Terephthalic Acid
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摘要:
目的 研究对苯二甲酸(terephthalic acid,TPA)促进膀胱癌发生的细胞周期调节机制。 方法 50只Wister大鼠分为实验组(30只)及对照组(20只),每周两次分别腹腔注射甲基亚硝基脲(MNU)和冰柠檬酸盐缓冲液,持续4周。在随后的22周,分别给大鼠饲以含5% TPA和0% TPA的饲料。利用免疫组织化学方法检查G1细胞周期关卡的主要调节蛋白包括抑癌基因p16INK4a蛋白(p16INK4a)、周期素依赖性蛋白激酶4(Cdk4)、细胞周期蛋白D1(cyclin D1)和成视网膜细胞瘤蛋白(pRb)在大鼠膀胱癌发生各个阶段的表达水平。 结果 5% MUN-TPA处理组,膀胱乳头状瘤中Cdk4、cyclin D1和pRb过度表达率显著高于它们在上皮单纯性增生(P=0.023,P < 0.001和P < 0.001)和乳头结节状增生(P=0.042,P=0.012和P=0.002)的表达率。膀胱乳头状瘤中p16INK4a的缺失表达率显著高于上皮单纯性增生(P=0.004)和乳头结节状增生(P=0.02)中的表达率。 结论 p16INK4a-cyclin D1和Cdk4复合物-pRb通路的紊乱参与了对苯二甲酸结石促进大鼠膀胱癌的发生过程。 Abstract:Objective To study the cell cycle regulatory mechanism in rat bladder carcinogenesis promoted by terephthalic acid (TPA). Methods A total of 50 male Wister rats were divided into test group (30 rats) and control group (20 rats), respectively intraperitoneally injected with N-methyl-N-nitrosourea (MNU) and citrate buffer twice a week for 4 weeks, and then basal diet containing 5%TPA were given to the test group and basal diet to the control group separately for the next 22 weeks. Major regulatory proteins in G1 cell cycle checkpoint including p16INK4a, cyclin-dependent kinase 4 (Cdk4), cyclin D1, and retinoblastoma protein (pRb) were determined during various stages of urinary bladder carcinogenesis by immunohistochemistry. Results In MNU-5% TPA treated group, the incidences of overexpression of Cdk4, cyclin D1 and pRb in papilloma were significantly higher than those in epithelial simple hyperplasia (P=0.023, P < 0.001 and P < 0.001, respectively) and in papillary or nodular (PN) hyperplasia (P=0.042, P=0.012 and P=0.002, respectively). The incidence of absent expression of p16INK4a in papilloma was much higher than that in epithelial simple hyperplasia (P=0.004) and in PN hyperplasia (P=0.02). Conclusion Our results clearly reveal that the disorder of p16INK4a-cyclin D1/Cdk4-pRb pathway is associated with bladder carcinogenesis promoted by TPA-stone.
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