Hinz S, Kempkensteffen C, Weikert S, Schostak M, Schrader M, Miller K, Christoph F
Department of Urology, Charité - Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Tumour Biol. 2007;28(3):151-7. doi: 10.1159/000103380. Epub 2007 Jun 1.
The EZH2 gene controls methylation of various EZH2 target promoters. The APAF-1, DAPK-1 und IGFBP-3 genes are frequently methylated in bladder cancer, and methylation of these genes is found in more aggressive tumor types. The aim of our study was to investigate a potential link between EZH2 mRNA expression and the extent of APAF-1, DAPK-1 and IGFBP-3 methylation in urothelial transitional cell carcinoma (TCC) and to correlate the data with histopathological parameters and follow-up data. EZH2 mRNA expression was measured by real-time reverse transcription polymerase chain reaction, and the methylation analysis was performed using methylation-specific real-time polymerase chain reaction. Tissue specimens were obtained from 35 patients with TCC. EZH2 mRNA expression was detected in all tumor specimens investigated. The EZH2 expression levels correlated well with the differentiation grade of the tumor specimens (p = 0.03), and the APAF-1 methylation correlated with tumor stage (p = 0.0001) and grade (p = 0.004). Matched pair analysis demonstrated a statistically significant correlation between elevated EZH2 mRNA expression and higher methylation levels of APAF-1 in superficial (p = 0.024) and well- differentiated (p = 0.04) TCC. In patients with recurrent TCC, APAF-1 and IGFBP-3 methylation levels were significantly higher (p = 0.03 and p = 0.01, respectively), which was not observed when EZH2 mRNA expression or DAPK-1 methylation levels were related to the clinical outcome. In conclusion, our data show that EZH2 expression and APAF-1 methylation are related to tumor progression and invasiveness. Moreover, these data present first evidence that APAF-1 methylation is related to transcriptional activity of EZH2 expression in early-stage tumor disease of the bladder.
EZH2基因控制着多种EZH2靶启动子的甲基化。APAF - 1、DAPK - 1和IGFBP - 3基因在膀胱癌中常发生甲基化，且在侵袭性更强的肿瘤类型中可发现这些基因的甲基化。我们研究的目的是探讨EZH2 mRNA表达与尿路上皮移行细胞癌（TCC）中APAF - 1、DAPK - 1和IGFBP - 3甲基化程度之间的潜在联系，并将数据与组织病理学参数及随访数据相关联。通过实时逆转录聚合酶链反应测量EZH2 mRNA表达，并使用甲基化特异性实时聚合酶链反应进行甲基化分析。从35例TCC患者获取组织标本。在所研究的所有肿瘤标本中均检测到EZH2 mRNA表达。EZH2表达水平与肿瘤标本的分化程度密切相关（p = 0.03），且APAF - 1甲基化与肿瘤分期（p = 0.0001）和分级（p = 0.004）相关。配对分析表明，在浅表性（p = 0.024）和高分化（p = 0.04）TCC中，EZH2 mRNA表达升高与APAF - 1较高的甲基化水平之间存在统计学上的显著相关性。在复发性TCC患者中，APAF - 1和IGFBP - 3甲基化水平显著更高（分别为p = 0.03和p = 0.01），而当EZH2 mRNA表达或DAPK - 1甲基化水平与临床结果相关时未观察到这种情况。总之，我们的数据表明EZH2表达和APAF - 1甲基化与肿瘤进展和侵袭性相关。此外，这些数据首次证明在膀胱早期肿瘤疾病中，APAF - 1甲基化与EZH2表达的转录活性相关。
