NGALR Is Overexpressed and Regulated by Hypomethylation in Esophageal Squamous Cell Carcinoma
NGALR Is Overexpressed and Regulated by Hypomethylation in Esophageal Squamous Cell Carcinoma
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DOI：
10.1158/1078-0432.ccr-08-0420
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发表时间：
2008-12-01
影响因子：
11.5
通讯作者：
Li, En-Min
中科院分区：
文献类型：
--
作者：
Cui, Lei;Xu, Li-Yan;Li, En-Min
目的：中性粒细胞明胶酶相关脂质运载蛋白受体（NGALR）mRNA水平在孤立的慢性髓细胞白血病母细胞中降低，但在食管鳞状细胞癌（ESCC）中上调NGALR调节的机制尚不清楚。在这里，我们显示NGALR的表达模式，并检查其基因在ESCC和食管癌细胞株的异常甲基化。实验设计：NGALR的表达模式进行了分析，通过免疫组化在59 ESCC和非癌组织相比。通过甲基化特异性PCR和亚硫酸氢盐基因组测序研究了食管癌细胞系和手术切除样品中的DNA甲基化状态。结果：食管鳞癌组织中NGALR在癌细胞膜和胞浆中的表达明显高于正常食管上皮（P < 0.01）;甲基化等位基因在三个NGALR非表达细胞系中检测到，但在三个NGALR表达细胞系中未检测到。用甲基化抑制剂5-氮杂-2 '-脱氧胞苷处理甲基化细胞系，恢复NGALR表达。在手术切除的食管癌组织中，NGALR等位基因甲基化率为40.3%（31/77），而正常食管组织中NGALR等位基因甲基化率为59.7%（46/77）（P < 0.05）。
Purpose: Neutrophil gelatinase-associated lipocalin receptor (NGALR) m RNA level is reduced in isolated chronic myelogenous leukemia blasts but up-regulated in esophageal squamous cell carcinoma (ESCC). The mechanism of NGALR regulation is unknown. Here, we show the expression pattern of NGALR and examine the aberrant methylation of its gene in ESCC and esophageal carcinoma cell lines.Experimental Design: The expression pattern of NGALR was analyzed by immunohistochemistry in 59 ESCCs and compared with noncancerous tissues. The DNA methylation status was investigated by methylation-specific PCR and by bisulfite genomic sequencing in esophageal carcinoma cell lines and surgically,resected samples. Methylated cell lines were treated with a methylation inhibitor to restore NGALR expression.Results: The expression of NGALR in ESCC was significantly higher in tumor cell membrane and cytoplasm than in normal esophageal epithelium (P < 0.01). Methylated alleles were detected in three NGALR-nonexpressing cell lines but were not detected in three NGALR-expressing cell lines. Treatment of methylated cell lines with 5-aza-2'-deoxycytidine, a methylation inhibitor, restored NGALR expression. In surgically resected samples, 31 of 77 (40.3%) primary esophageal carcinomas and 46 of 77 (59.7%) paired normal tissues contained methylated NGALR alleles (P < 0.05).Conclusions: Our results suggest that NGALR hypomethylation contributes to its expression in esophageal carcinomas and that this overexpression may play a role in the pathogenesis of esophageal carcinomas.