GATA-4 和 GATA-5 的甲基化与散发性胃癌的发生发展。
Methylation of GATA-4 and GATA-5 and development of sporadic gastric carcinomas.
机构信息
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Etiology, Peking University School of Oncology and Beijing Cancer Hospital & Institute, Fucheng Road No. 52, Haidian District, Beijing 100142, China.
出版信息
World J Gastroenterol. 2010 Mar 14;16(10):1201-8. doi: 10.3748/wjg.v16.i10.1201.
AIM
To understand the implication of GATA-4 and GATA-5 methylation in gastric carcinogenesis.
METHODS
Methylation status of GATA-4 and GATA-5 CpG islands in human gastric mucosa samples, including normal gastric biopsies from 45 outpatients, gastric dysplasia [low-grade gastric intraepithelial neoplasia (GIN), n = 30; indefinite, n = 77], and 80 paired sporadic gastric carcinomas (SGC) as well as the adjacent non-neoplastic gastric tissues was analyzed by methylation specific polymerase chain reaction (MSP) and confirmed by denatured high performance liquid chromatography (DHPLC). Immunohistochemical staining was used to detect protein expression. The correlation between GATA-4 and GATA-5 methylation and clinicopathological characteristics of patients including Helicobacter pylori (H. pylori) infection was analyzed.
RESULTS
GATA-4 and GATA-5 methylation was frequently observed in SGCs (53.8% and 61.3%, respectively) and their corresponding normal tissues (41.3% and 46.3%) by MSP. The result of MSP was consistent with that of DHPLC. Loss of both GATA-4 and GATA-5 proteins was associated with their methylation in SGCs (P = 0.01). Moreover, a high frequency of GATA-4 and GATA-5 methylation was found in both gastric low-grade GIN (57.1% and 69.0%) and indefinite for dysplasia (42.9% and 46.7%), respectively. However, GATA-4 and GATA-5 methylation was detected only in 4/32 (12.5%) and 3/39 (7.7%) of normal gastric biopsies. GATA-4 methylation in both normal gastric mucosa and low-grade GIN was also significantly associated with H. pylori infection (P = 0.023 and 0.027, two-sides).
CONCLUSION
Epigenetic inactivation of GATA-4 (and GATA-5) by methylation of CpG islands is an early frequent event during gastric carcinogenesis and is significantly correlated with H. pylori infection.
目的
了解 GATA-4 和 GATA-5 甲基化在胃癌发生中的意义。
方法
采用甲基化特异性聚合酶链反应（MSP）分析 45 例门诊患者正常胃黏膜活检标本（正常胃黏膜组织 n=45）、胃低级别上皮内瘤变（LGIN）[低级别胃上皮内肿瘤（LGIN），n=30；不确定，n=77]和 80 对散发性胃癌（SGC）及其相邻非肿瘤性胃组织中 GATA-4 和 GATA-5 CpG 岛的甲基化状态，并通过变性高效液相色谱（DHPLC）进行验证。采用免疫组织化学染色检测蛋白表达。分析 GATA-4 和 GATA-5 甲基化与患者临床病理特征（包括幽门螺杆菌（H. pylori）感染）的相关性。
结果
MSP 检测发现 SGC 及其相应正常组织中 GATA-4 和 GATA-5 甲基化发生率分别为 53.8%和 61.3%（n=80）及 41.3%和 46.3%（n=45）。MSP 结果与 DHPLC 结果一致。SGC 中 GATA-4 和 GATA-5 蛋白缺失与甲基化有关（P=0.01）。此外，LGIN 和不确定的胃上皮内瘤变中 GATA-4 和 GATA-5 甲基化发生率较高，分别为 57.1%和 69.0%（n=30）及 42.9%和 46.7%（n=77）。然而，在 32 例正常胃黏膜活检标本和 39 例 LGIN 活检标本中，分别仅检测到 4/32（12.5%）和 3/39（7.7%）存在 GATA-4 甲基化。正常胃黏膜和 LGIN 中的 GATA-4 甲基化也与 H. pylori 感染显著相关（P=0.023 和 0.027，双侧）。
结论
GATA-4（和 GATA-5）CpG 岛甲基化导致的表观遗传学失活是胃癌发生过程中的早期高频事件，与 H. pylori 感染显著相关。
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