Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous cell carcinoma
Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous cell carcinoma
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DOI：
10.1093/carcin/bgq053
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发表时间：
2010-06-01
期刊：
影响因子：
4.7
通讯作者：
Inazawa, Johji
中科院分区：
文献类型：
--
作者：
Haruki, Shigeo;Imoto, Issei;Inazawa, Johji
原钙粘蛋白是钙粘蛋白超家族的一个亚家族，但对其功能知之甚少。在筛选一组食管鳞状细胞癌（ESCC）细胞系基因组拷贝数畸变的过程中，我们发现了原钙粘蛋白（PCDH）17的纯合缺失。PCDH 17信使RNA在正常食管组织中表达，但在大多数ESCC细胞系中不表达，而在该基因纯合缺失的情况下，在用5-氮杂-2 '-脱氧胞苷处理后，在基因沉默的ESCC细胞中恢复。PCDH 17 CpG岛的DNA甲基化状态与PCDH 17表达呈负相关，并且推定的甲基化靶区域显示启动子活性。PCDH 17基因启动子甲基化也与原发性食管鳞癌中基因表达的沉默有关。在原发性ESCC病例中，PCDH 17蛋白表达的沉默与ESCC细胞的较差分化状态相关，并可能与该肿瘤亚群的预后相关。ESCC细胞中PCDH 17表达的恢复减少了细胞增殖和迁移/侵袭。这些结果表明，沉默PCDH 17的表达，通过启动子的超甲基化或其他机制，导致其肿瘤抑制活性的损失，这可能是一个因素，在一个亚组的食管鳞癌的致癌作用。
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.