Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Carcinogenesis. 2010 Jun;31(6):1027-36. doi: 10.1093/carcin/bgq053. Epub 2010 Mar 3.
Protocadherins are a subfamily of the cadherin superfamily, but little is known about their functions. We identified a homozygous loss of protocadherin (PCDH) 17 in the course of a program to screen a panel of esophageal squamous cell carcinoma (ESCC) cell lines for genomic copy number aberrations. PCDH17 messenger RNA was expressed in normal esophageal tissue but not in the majority of ESCC cell lines without a homozygous deletion of this gene and restored in gene-silenced ESCC cells after treatment with 5-aza-2'-deoxycytidine. The DNA methylation status of the PCDH17 CpG island correlated inversely with the PCDH17 expression, and a putative methylation target region showed promoter activity. The methylation of the PCDH17 promoter was also associated with the silencing of gene expression in primary ESCC partly. Among primary ESCC cases, the silencing of PCDH17 protein expression was associated with a poorer differentiation status of ESCC cells and possibly with prognosis in a subset of this tumour. Restoration of PCDH17 expression in ESCC cells reduced cell proliferation and migration/invasion. These results suggest that silencing of PCDH17 expression through hypermethylation of the promoter or other mechanisms leads to loss of its tumour-suppressive activity, which may be a factor in the carcinogenesis of a subgroup of ESCCs.
原钙黏蛋白是钙黏蛋白超家族的一个亚家族，但对其功能知之甚少。我们在对一组食管鳞状细胞癌 (ESCC) 细胞系进行基因组拷贝数异常筛选的过程中发现，原钙黏蛋白 (PCDH) 17 发生纯合缺失。PCDH17 信使 RNA 在正常食管组织中表达，但在大多数没有该基因纯合缺失的 ESCC 细胞系中不表达，在用 5-氮杂-2'-脱氧胞苷处理后，基因沉默的 ESCC 细胞中恢复表达。PCDH17 CpG 岛的 DNA 甲基化状态与 PCDH17 表达呈负相关，并且推定的甲基化靶区显示启动子活性。PCDH17 启动子的甲基化也与原发性 ESCC 中部分基因表达沉默有关。在原发性 ESCC 病例中，PCDH17 蛋白表达的沉默与 ESCC 细胞分化程度较差有关，并且在该肿瘤的亚组中可能与预后有关。在 ESCC 细胞中恢复 PCDH17 表达可降低细胞增殖和迁移/侵袭。这些结果表明，通过启动子的高甲基化或其他机制导致 PCDH17 表达沉默，从而丧失其肿瘤抑制活性，这可能是 ESCC 亚组发生癌变的一个因素。
