Kunze Ekkehard, Von Bonin Frederike, Werner Carola, Wendt Maike, Schlott Thilo
Center of Pathology, University of Göttingen, D-37099 Göttingen, Germany.
Int J Mol Med. 2006 Jan;17(1):3-13.
Tumor suppressor genes play a prominent role in the modification and progression of urinary bladder carcinogenesis as a result of classic genetic alterations. Little is known about the potential significance of epigenetic events, mediated by DNA hypermethylation. This prompted our investigation to explore the global Alu methylation and the promoter methylation of the novel putative tumor suppressor genes caveolin-1 and hDAB2IP, and of p53 in transitional cell carcinomas (TCC), squamous cell carcinomas and undifferentiated small cell carcinomas of the urinary bladder. Quantitative GeneScan analysis revealed that the various histopathological tumor entities showed considerable interindividual variations in the global methylation, but the overall rate did not significantly differ between the various cancer subtypes. With methylation-specific PCR, a high frequency of methylation of the promoter region of the caveolin-1 gene was detected in undifferentiated small cell carcinomas (50%) and in squamous cell carcinomas (25.9%), while TCC were found not to be methylated. By immunohistochemistry, all squamous cell carcinomas showed a strong diffuse overexpression of caveolin-1, whereas undifferentiated small cell cancers lacked any expression. High-grade, high-stage TCC disclosed a higher incidence (60%) and a substantially stronger expression than low-grade, low-stage TCC (42.9%). Our findings suggest that hypermethylation of the caveolin-1 gene and an abnormal protein expression play a crucial role in cell differentiation, and in the phenotypical conversion of TCC into nonurothelial carcinomas. Promoter methylation of the hDAB2IP gene occurred more frequently in advanced muscle invasive (72.7%) than in superficial noninvasive (50%) TCC. DNA hypermethylation of p53 was detected in a quarter of the low-grade, low-stage TCC and undifferentiated small cell carcinomas, but only sporadically in squamous cell carcinomas, and was absent in high-grade, high-stage TCC. In conclusion, aberrant methylation and abnormal protein expression of the caveolin-1-gene is involved in the formation of nonurothelial carcinomas of the urinary bladder and promoter methylation of the hDAB2IP gene in the progression of TCC from a low to a high malignant potential.
由于经典的基因改变，肿瘤抑制基因在膀胱癌发生的修饰和进展中发挥着重要作用。关于由DNA高甲基化介导的表观遗传事件的潜在意义知之甚少。这促使我们进行研究，以探索新型假定肿瘤抑制基因小窝蛋白-1（caveolin-1）、hDAB2IP以及p53在膀胱移行细胞癌（TCC）、鳞状细胞癌和未分化小细胞癌中的整体Alu甲基化和启动子甲基化情况。定量基因扫描分析显示，各种组织病理学肿瘤实体在整体甲基化方面表现出相当大的个体间差异，但不同癌症亚型之间的总体发生率没有显著差异。通过甲基化特异性PCR，在未分化小细胞癌（50%）和鳞状细胞癌（25.9%）中检测到小窝蛋白-1基因启动子区域的高甲基化频率，而TCC未发现甲基化。通过免疫组织化学，所有鳞状细胞癌均显示小窝蛋白-1强烈弥漫性过表达，而未分化小细胞癌则无任何表达。高级别、高分期的TCC比低级别、低分期的TCC显示出更高的发生率（60%）和更强的表达（42.9%）。我们的研究结果表明，小窝蛋白-1基因的高甲基化和异常蛋白表达在细胞分化以及TCC向非尿路上皮癌的表型转化中起关键作用。hDAB2IP基因的启动子甲基化在晚期肌肉浸润性TCC（72.7%）中比浅表非浸润性TCC（50%）中更频繁发生。在四分之一的低级别、低分期TCC和未分化小细胞癌中检测到p53的DNA高甲基化，但在鳞状细胞癌中仅偶尔检测到，在高级别、高分期TCC中未检测到。总之，小窝蛋白-1基因的异常甲基化和异常蛋白表达参与了膀胱非尿路上皮癌的形成，hDAB2IP基因的启动子甲基化参与了TCC从低恶性潜能向高恶性潜能的进展。
