Department of Urology, Chang Gung Memorial Hospital, Keelung, Taiwan.
Cancer. 2011 Nov 15;117(22):5221-33. doi: 10.1002/cncr.26150. Epub 2011 Apr 26.
The identification of potential tumor markers will help improve therapeutic planning and patient management. Therefore, the aim of this study was to highlight the role of DNA methyltransferase 1 (DNMT1) in bladder cancer.
A total of 50 samples of nonmalignant urothelium, 65 of muscle-invasive bladder cancers, 15 of distant metastasis, and 50 of nonmuscle-invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments investigating changes in tumor behavior, treatment response, and related signaling in bladder cancer.
The incidence of nuclear DNMT1 immunoreactivity in the bladder cancer specimens (45%) was significantly higher than in nonmalignant urothelium (15%, P = .0005), and the incidence in cancer was positively linked to clinical stage (24% in ≤T1 vs 55% in T2-T4, P = .0007). The staining of DNMT1 was also significantly linked to lower complete response rates (P = .0014) and reduced survival rates (P = .000). By in vitro and in vivo experiments, DNMT1 silencing vector reduced tumor growth and attenuated treatment resistance in bladder cancer cells. Less epithelial-mesenchymal transition, less invasion, and slower tumor growth were noted in cancer cells with inhibited DNMT1. Furthermore, the epidermal growth factor receptor-mediated phosphatidylinositol 3'-kinase-protein kinase B pathway might be the mechanism underlying the effects of DNMT1 on bladder cancer.
DNMT1 could be a significant clinical predictor for stage and treatment response of bladder cancer. Moreover, targeting this enzyme could be a promising strategy for treating bladder cancer, as evidenced by inhibited tumor growth and enhanced radiosensitivity.
鉴定潜在的肿瘤标志物将有助于改善治疗计划和患者管理。因此，本研究旨在强调 DNA 甲基转移酶 1（DNMT1）在膀胱癌中的作用。
选择 50 例非恶性尿路上皮、65 例肌层浸润性膀胱癌、15 例远处转移和 50 例非肌层浸润性膀胱癌样本进行免疫组织化学染色分析。此外，选择人膀胱癌细胞系 HT1376 和 HT1197 进行细胞和动物实验，研究膀胱癌中肿瘤行为、治疗反应和相关信号的变化。
膀胱癌标本中核 DNMT1 免疫反应性的发生率（45%）明显高于非恶性尿路上皮（15%，P =.0005），且在癌症中的发生率与临床分期呈正相关（≤T1 为 24%，T2-T4 为 55%，P =.0007）。DNMT1 的染色也与较低的完全缓解率（P =.0014）和生存率降低（P =.000）显著相关。通过体外和体内实验，DNMT1 沉默载体减少了膀胱癌细胞的肿瘤生长并减弱了治疗耐药性。抑制 DNMT1 的癌细胞中，上皮-间充质转化减少，侵袭减少，肿瘤生长较慢。此外，表皮生长因子受体介导的磷脂酰肌醇 3'-激酶-蛋白激酶 B 通路可能是 DNMT1 对膀胱癌影响的机制。
DNMT1 可能是膀胱癌分期和治疗反应的重要临床预测因子。此外，靶向该酶可能是治疗膀胱癌的一种有前途的策略，因为它可以抑制肿瘤生长和增强放射敏感性。
