Jin Zhe, Hamilton James P, Yang Jian, Mori Yuriko, Olaru Alexandru, Sato Fumiaki, Ito Tetsuo, Kan Takatsugu, Cheng Yulan, Paun Bogdan, David Stefan, Beer David G, Agarwal Rachana, Abraham John M, Meltzer Stephen J
Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, 1503 East Jefferson Street, Baltimore, MD 21231, USA.
Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):111-7. doi: 10.1158/1055-9965.EPI-07-0407.
The A-kinase anchoring protein 12 (AKAP12) is a kinase scaffold protein with known tumor suppressor activity. Recently, AKAP12 promoter hypermethylation was reported in gastric and colorectal cancers. We examined AKAP12 promoter hypermethylation using real-time methylation-specific PCR in 259 human esophageal tissues. AKAP12 hypermethylation showed highly discriminative receiver-operator characteristic (ROC) curve profiles, clearly distinguishing esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma and normal esophagus (P < 0.0001). AKAP12-normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's, and EAC than in normal esophagus (P < 0.0000001). AKAP12 hypermethylation frequency was zero in normal esophagus but increased early during neoplastic progression, to 38.9% in BE from patients with Barrett's alone, 52.5% in dysplastic Barrett's metaplasia, and 52.2% in EAC. AKAP12 hypermethylation levels were significantly higher in normal esophageal epithelia from patients with EAC (mean = 0.00082) than in normal esophagi from patients without Barrett's or esophageal cancer (mean = 0.00007; P = 0.006). There was a significant correlation between AKAP12 hypermethylation and BE segment length, a known clinical neoplastic progression risk factor. In contrast, only 2 (7.7%) of 26 esophageal squamous cell carcinomas exhibited AKAP12 hypermethylation. Treatment of BIC and OE33 EAC cells with 5-aza-2'-deoxycytidine reduced AKAP12 methylation and increased AKAP12 mRNA expression. AKAP12 mRNA levels in EACs with unmethylated AKAP12 (mean = 0.1663) were higher than in EACs with methylated AKAP12 (mean = 0.0668). We conclude that promoter hypermethylation of AKAP12 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker for the early detection of EAC.
A激酶锚定蛋白12（AKAP12）是一种具有已知肿瘤抑制活性的激酶支架蛋白。最近，在胃癌和结直肠癌中报道了AKAP12启动子高甲基化。我们使用实时甲基化特异性PCR检测了259例人食管组织中的AKAP12启动子高甲基化。AKAP12高甲基化显示出高度有鉴别力的受试者工作特征（ROC）曲线图谱，能清楚地区分食管腺癌（EAC）与食管鳞状细胞癌和正常食管（P < 0.0001）。与正常食管相比，Barrett化生（BE）、发育异常的Barrett化生和EAC中AKAP12标准化甲基化值显著更高（P < 0.0000001）。正常食管中AKAP12高甲基化频率为零，但在肿瘤进展早期增加，仅患有Barrett化生的患者中BE的高甲基化频率为38.9%，发育异常的Barrett化生中为52.5%，EAC中为52.2%。EAC患者的正常食管上皮中AKAP12高甲基化水平（平均值 = 0.00082）显著高于无Barrett化生或食管癌患者的正常食管（平均值 = 0.00007；P = 0.006）。AKAP12高甲基化与BE段长度之间存在显著相关性，BE段长度是已知的临床肿瘤进展风险因素。相比之下，26例食管鳞状细胞癌中只有2例（7.7%）表现出AKAP12高甲基化。用5-氮杂-2'-脱氧胞苷处理BIC和OE33 EAC细胞可降低AKAP12甲基化并增加AKAP12 mRNA表达。AKAP12未甲基化的EAC中AKAP12 mRNA水平（平均值 = 0.1663）高于AKAP12甲基化的EAC（平均值 = 0.0668）。我们得出结论，AKAP12启动子高甲基化是人类EAC中常见的组织特异性事件，发生在与Barrett化生相关的食管肿瘤进展早期，是EAC早期检测的潜在生物标志物。
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