Prediction of prognosis and clinical application of gene methylation score in urothelial cancers

目的：近年来，许多与膀胱癌进展有关的基因被分离出来。我们已经报道了两个抑癌基因p16INK4a和p14ARF的甲基化与膀胱癌患者的不良预后和肿瘤侵袭性有关。在本研究中，我们研究了胶原1A2基因启动子区的甲基化状态在预测患者预后方面。材料和方法：我们研究了胶原1A2基因甲基化状态的存在和不存在的去甲基化剂，5氮胞苷在人BOY培养的膀胱癌细胞。我们检测了97例根治性膀胱癌和TURBT的临床标本中胶原1A2基因甲基化的频率。结果：5氮胞苷处理后，1A2胶原基因表达增加，细胞迁移能力增强，细胞生长速度加快。膀胱肿瘤组织中胶原1A2基因表达明显低于正常膀胱组织。膀胱肿瘤组织的甲基化评分明显高于正常膀胱组织。结论：1A2基因启动子区甲基化抑制了人膀胱癌组织中1A2基因的表达。提示胶原1A2基因在膀胱癌中起抑癌作用。

Purpose : Many genes responsible for the bladder cancer progression have been isolated recently. We have reported thathypermethylation of 2 tumor suppressor genes, pl6INK4a and p14ARF is involved in poor prognosis and tumor invasiveness in patients with bladder cancer. In the present study, we examined methylation status of collagen 1A2 gene promoter region in terms of prediction of patient prognosis.Materials and Methods : We examined methylation status of collagen 1A2 gene in the presence and absence of demethylation agent, 5 aza-cytizine in human BOY cultured bladder cancer cells. We examined the frequency of methylation of collagen 1A2 gene in 97 clinical specimens from radical cystectomy and TURBT. Furthermore, we transfected collagen 1A2 gene into human bladder cancer cells and examined cell migration ability and growth rate in both transfectants and control cells.Results : Gene expression of collagen 1A2 gene was increased by 5 aza-cytizine treatment. Collagen 1A2 gene expression in bladder tumors was significantly lower than that in normal bladder tissues. Methylation scores in the bladder tumors are significantly higher that those in normal bladder tissues. Cell migration and growth rate in collagen 1A2 gene transfectants are significantly decreased compared to those in control cells.Conclusions : Collagen 1A2 gene expression is suppressed by the promoter methylation in human bladder cancers. These results suggest that collagen 1A2 gene plays a role in tumor suppressor in human bladder cancer.