GATA4 and GATA5 are Potential Tumor Suppressors and Biomarkers in Colorectal Cancer
GATA4 and GATA5 are Potential Tumor Suppressors and Biomarkers in Colorectal Cancer
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DOI：
10.1158/1078-0432.ccr-09-0055
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发表时间：
2009-06-15
影响因子：
11.5
通讯作者：
van Engeland, Manon
中科院分区：
文献类型：
--
作者：
Hellebrekers, Debby M. E. I.;Lentjes, Marjolein H. F. M.;van Engeland, Manon
目的：转录因子GATA 4和GATA 5参与胃肠发育，并在结直肠癌中因启动子超甲基化而失活。在这里，我们评估了GATA 4/5启动子甲基化作为潜在的生物标志物的非侵袭性结直肠癌检测，并探讨了GATA 4/5在结直肠cancer.Experimental Design的作用：启动子甲基化的GATA 4/5进行了分析，结直肠癌患者和健康对照组的结直肠组织和粪便DNA甲基化特异性PCR。结果：GATA 4/5甲基化在大肠癌中的表达率分别为70%（63/90）和79%（61/77），且与临床病理特征无关。非癌对照的正常结肠组织中甲基化频率分别为6%（5/88，GATA 4; P < 0.001）和13%（13/100，GATA 5; P < 0.001）。GATA 4/5过表达抑制大肠癌细胞的集落形成（P < 0.005）、增殖（P < 0.001）、迁移（P <0.05）、侵袭（P < 0.05）和非贴壁依赖性生长（P < 0.0001）。两个独立系列的结直肠癌患者和对照组粪便DNA中GATA 4甲基化检测的敏感性为71% [95%置信区间（95%CI），55-88%]，特异性为84%。（95%CI，74-95%）用于训练集中的结直肠癌检测，灵敏度为51%结论：GATA 4/5甲基化是大肠癌中常见的特异性事件，GATA 4/5在体外对大肠癌细胞具有肿瘤抑制作用。粪便DNA中的GATA 4甲基化可能对结直肠癌检测有意义。
Purpose: The transcription factors GATA4 and GATA5 are involved in gastrointestinal development and are inactivated by promoter hypermethylation in colorectal cancer. Here, we evaluated GATA4/5 promoter methylation as potential biomarkers for noninvasive colorectal cancer detection, and investigated the role of GATA4/5 in colorectal cancer.Experimental Design: Promoter methylation of GATA4/5 was analyzed in colorectal tissue and fecal DNA from colorectal cancer patients and healthy controls using methylation-specific PCR. The potential function of GATA4/5 as tumor suppressors was studied by inducing GATA4/5 overexpression in human colorectal cancer cell lines.Results: GATA4/5 methylation was observed in 70% (63/90) and 79% (61/77) of colorectal carcinomas, respectively, and was independent of clinicopathologic features. Methylation frequencies in normal colon tissues from noncancerous controls were 6% (5 of 88, GATA4; P < 0.001) and 13% (13 of 100, GATA5; P < 0.001). GATA4/5 overexpression suppressed colony formation (P < 0.005), proliferation (P < 0.001), migration (P < 0.05), invasion (P < 0.05), and anchorage-independent growth (P < 0.0001) of colorectal cancer cells. Examination of GATA4 methylation in fecal DNA from two independent series of colorectal cancer patients and controls yielded a sensitivity of 71% [95% confidence interval (95% Cl), 55-88%] and specificity of 84% (95% Cl, 74-95%) for colorectal cancer detection in the training set, and a sensitivity of 51% (95% Cl, 37-65%) and specificity of 93% (95% Cl, 84-100%) in the validation set.Conclusions: Methylation of GATA4/5 is a common and specific event in colorectal carcinomas, and GATA4/5 exhibit tumor suppressive effects in colorectal cancer cells in vitro. GATA4 methylation in fecal DNA may be of interest for colorectal cancer detection.