目的：探讨人贲门腺癌（gastric cardia adenocarcinoma，GCA）组织中胰岛素样生长因子结合蛋白-7（insulin-like growth factor binding protein 7， IGFBP7）基因启动子区及第1外显子区甲基化状态及其与IGFBP7蛋白表达之间的关系。方法：选取河北医科大学第四医院2009年4月至2011年12月间收治的85例GCA患者癌组织标本和67例癌旁组织标本。采用甲基化特异性聚合酶链式反应（methylation specific polymerase chain reaction，MSP）方法、RT-PCR及免疫组织化学法检测IGFBP7基因在GCA组织及癌旁组织中的甲基化情况、IGFBP7mRNA及蛋白的表达。结果：GCA组织中IGFBP7基因启动子区甲基化率为52.9%（45/85），第1外显子5′非翻译区的甲基化率为35.3%（30/85），相应癌旁组织IGFBP7基因启动子区及第1外显子5′非翻译区的甲基化率分别为35.8%（24/67）和19.4%（13/67）；癌组织IGFBP7基因启动子区及第1外显子5′非翻译区的甲基化率明显高于癌旁组织（P<0.05），且GCA组织中IGFBP7基因启动子区甲基化率显著高于第1外显子区（P<005）。GCA组织中IGFBP7 mRNA和蛋白表达显著低于癌旁组织（P<0.05），且与其启动子区甲基化状态呈负相关。结 论：GCA组织中IGFBP7基因启动子区比第1外显子区更易发生甲基化而导致IGFBP7表达缺失，IGFBP7基因启动子区异常高甲基化可能是GCA发生的机制之一。

Objective:To investigate the promoter and exon1 methylation of insulin-like growth factor binding protein 7 ( IGFBP7 ) gene and its correlation with the expression of IGFBP7 protein in gastric cardia adenocarcinoma (GCA) tissues. Methods: Eighty-five GCA samples and 67 paracancerous tissues from GCA patients (who had been diagnosed in the Forth Hospital of Hebei Medical University, from April, 2009 to December, 2011) were included in the present study. Methylation specific polymerase chain reaction (MSP), RT-PCR and immunohistochchemistry methods were respectively used to examine the methylation status, mRNA and protein expressions of IGFBP7 in GCA tissues and paracancerous tissues. Results: For the promoter site, the methylation frequency of IGFBP7 gene in the GCA specimens (52.9%, 45/85) was significantly higher than that in the paracancerous tissues (35.8%, 24/67) (P<005). For the 5′ UTR of exon1, the methylation frequency of IGFBP7 gene in the GCA specimens (35.3%, 30/85) was significantly higher than that in the paracancerous tissues (19.4%, 13/67) (P<0.05). The methylation frequency of IGFBP7 gene in the promoter site was significantly higher than that in the 5′ UTR of exon1 (P<0.05). The mRNA and protein expressions of IGFBP7 in the GCA tissues were significantly higher than those in the paracancerous tissues (P<0.05) and were inversely correlated with the methylation status of promoter. Conclusion: Compared to the exon1, IGFBP7 promoter site is more likely to be methylated in GCA tissues and may play an important role in the down-regulation of IGFBP7 in GCA tumorigenesis. Hypermethylation of IGFBP7 in promoter site may be one of the mechanisms leading to the occurrence of GCA.

河北省科技厅科技支撑课题资助（No. 072761223）