Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer
Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer
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DOI：
10.1002/ijc.22828
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发表时间：
2007-09-15
影响因子：
6.4
通讯作者：
Herman, James G.
中科院分区：
文献类型：
--
作者：
Guo, MingZhou;House, Michael G.;Herman, James G.
CDX2是哺乳动物同源盒基因“尾端”的同源物，在肠道上皮中表达，在发育过程中建立肠道表型中起重要作用。CDX2杂合破坏的小鼠发生无组织的息肉样错构瘤，具有腺上皮和类似前肠粘膜的分层鳞状化生。由于没有CDX2的遗传破坏被报道来解释基因功能的丧失，我们研究了表观遗传机制是否改变了CDX2的表达。17个鳞状食管癌细胞系中有11个缺乏CDX2的表达，在5-aza-2'-脱氧胞苷治疗后恢复，而所有结直肠癌细胞系均表达CDX2。通过甲基化特异性PCR和亚硫酸盐测序发现，表达缺失与CDX2 5'区DNA甲基化有关。CDX2甲基化在原发结直肠癌（44例中有1例，2%）和食管腺癌（43例中有2例，5%）中少见，但在食管鳞状癌（45例中有24例，49%）中常见。正常组织中未发现CDX2甲基化。采用半定量RT-PCR技术，CDX2在正常食管中表达水平较低，在原发性食管腺癌中表达水平较高，而在原发性食管鳞状癌中表达水平不高。CDX2在沉默细胞系中的恢复导致CDX2靶基因MUC2的表达，MUC2是一个在腺体分化中重要的基因。我们的研究结果表明，与DNA甲基化相关的食管癌中l的失活可能是鳞状或非腺瘤表型的重要决定因素。(c) 2007 Wiley-Liss, Inc。
CDX2, a mammalian homologue of the homeobox gene 'caudal,' is expressed in gut epithelia and plays an important role in establishing the intestinal phenotype during development. Mice heterozygously disrupted for CDX2 develop disorganized polypoid hamartomas with glandular epithelium and stratified squamous metaplasia resembling foregut mucosa. Since no genetic disruptions of CDX2 have been reported to explain loss of gene function, we examined whether epigenetic mechanisms altered CDX2 expression. Eleven of 17 squamous esophageal cancer cell lines lacked expression of CDX2 that was restored following treatment with 5-aza-2'-deoxycytidine, while all colorectal cancer cell lines expressed CDX2. Loss of expression was associated with DNA methylation in the 5' region of CDX2 determined by methylation specific PCR and bisulfite sequencing. Methylation of CDX2 was rare in primary colorectal (I of 44 tumors, 2%) and esophageal adenocarcinoma neoplasms (2 of 43 tumors, 5%), but was common in esophageal squamous carcinoma (24 of 45 tumors, 49%). No CDX2 methylation was found in normal tissues. Using semi-quantitative RT-PCR, expression of CDX2 was found in low level in normal esophagus, at higher levels in primary adenocarcinoma of the esophagus, but not in primary squamous cancers of the esophagus. Restoration of CDX2 in silenced cell lines resulted in expression of the CDX2 target gene MUC2, a gene important in glandular differentiation. Our results suggest that the inactivation of l in esophageal cancer associated with DNA methylation may be an important determinant of the squamous or non-adenomatous phenotype. (c) 2007 Wiley-Liss, Inc.