Bornman D M, Mathew S, Alsruhe J, Herman J G, Gabrielson E
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Am J Pathol. 2001 Sep;159(3):831-5. doi: 10.1016/S0002-9440(10)61758-0.
Decreased expression of the epithelial cell adhesion protein E-Cadherin occurs in several forms of human epithelial-derived cancers, including bladder cancers. We investigated the possibility that aberrant methylation of the CpG island flanking the 5' transcriptional start site of the e-cadherin gene is responsible for the decreased expression of this gene in bladder cancer, similar to the relationship previously seen between e-cadherin methylation and gene expression in other types of human cancers. Using methylation-specific polymerase chain reaction, we found methylation of this CpG island in 20 of 47 cases (43%) of bladder neoplasms ranging from low-grade papillary neoplasms to advanced, invasive cancers. When methylation status was compared to immunochemical staining for E-Cadherin, we found significantly diminished levels of E-Cadherin expression in 14 of 15 cases (93%) with methylation of the gene. We also found decreased expression of E-Cadherin, although to a somewhat lesser extent, in a high percentage (77%) of the cases without methylation of the gene. Although these data suggest a relationship between e-cadherin CpG island methylation and decreased gene expression, it evident that other mechanisms also contribute to decreased expression of this gene in bladder neoplasia. Remarkably, we also found low levels of e-cadherin methylation in urothelial cells from three of nine (33%) histologically normal bladders, with all three of the normal bladder samples with methylated e-cadherin being from individuals older than 70 years of age. Thus, methylation of the e-cadherin CpG island may occur normally in this tissue with aging as well as in low-grade papillary neoplasms, and is not specific to cancer in the bladder. This finding of methylation in normal urothelial cells from elderly individuals is provocative with respect to a possible link between aging and increased risk for bladder cancer, but it suggests limitations on the usefulness of using methylation of e-cadherin as a molecular marker for detection of bladder cancer.
上皮细胞粘附蛋白E-钙粘蛋白的表达降低出现在多种人类上皮源性癌症中，包括膀胱癌。我们研究了一种可能性，即E-钙粘蛋白基因5'转录起始位点侧翼的CpG岛异常甲基化是导致该基因在膀胱癌中表达降低的原因，这类似于先前在其他类型人类癌症中观察到的E-钙粘蛋白甲基化与基因表达之间的关系。使用甲基化特异性聚合酶链反应，我们在47例膀胱肿瘤（从低级别乳头状肿瘤到晚期浸润性癌症）中的20例（43%）中发现了该CpG岛的甲基化。当将甲基化状态与E-钙粘蛋白的免疫化学染色进行比较时，我们发现在15例（93%）基因甲基化的病例中有14例E-钙粘蛋白表达水平显著降低。我们还发现，在该基因未甲基化的病例中，有很高比例（77%）的病例E-钙粘蛋白表达也降低，尽管程度稍轻。虽然这些数据表明E-钙粘蛋白CpG岛甲基化与基因表达降低之间存在关联，但显然其他机制也导致了该基因在膀胱肿瘤形成过程中的表达降低。值得注意的是，我们还在9例（33%）组织学正常膀胱的尿路上皮细胞中发现了低水平的E-钙粘蛋白甲基化，所有3例E-钙粘蛋白甲基化的正常膀胱样本均来自70岁以上的个体。因此，E-钙粘蛋白CpG岛的甲基化可能在该组织中随着衰老以及在低级别乳头状肿瘤中正常发生，并非膀胱癌所特有。老年人正常尿路上皮细胞中甲基化的这一发现对于衰老与膀胱癌风险增加之间可能的联系具有启发性，但这也表明将E-钙粘蛋白甲基化用作膀胱癌检测分子标志物的实用性存在局限性。
