Carvalho Ralph, Kayademir Tuncay, Soares Paula, Canedo Paulo, Sousa Sónia, Oliveira Carla, Leistenschneider Peter, Seruca Raquel, Gött Peter, Blin Nikolaus, Carneiro Fátima, Machado José Carlos
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
Lab Invest. 2002 Oct;82(10):1319-26. doi: 10.1097/01.lab.0000029205.76632.a8.
It has been advanced that the trefoil factor (TFF) 1 gene is a candidate tumor-suppressor gene and may be involved in the development and/or progression of human gastric cancer. We aimed to clarify the putative role of TFF1 in gastric carcinogenesis. Ninety gastric carcinomas and eight gastric carcinoma-derived cell lines were screened for TFF1 mutations; subsets of the primary tumors and of the cell lines were subjected to loss of heterozygosity (LOH), immunohistochemistry, and promoter methylation analyses. TFF1 mutations were not detected in any of 90 gastric carcinomas. Eight (28%) of 28 informative cases displayed LOH at the TFF1 locus and absence of TFF1 staining by immunohistochemistry. These results indicate a frequent loss of TFF1 expression in gastric carcinomas through a mutation-independent mechanism. Extensive TFF1 promoter methylation was observed in nonexpressing gastric carcinoma-derived cell lines and tissues. Expressing cell lines, as well as normal gastric mucosa, presented little or no methylation of the promoter. Gastric carcinoma DNA presented de novo methylation of the promoter. These results point to the involvement of promoter methylation in the shutting down of TFF1. We conclude that TFF1 point mutations seem to be a rare event in gastric carcinogenesis. The loss of expression of TFF1 in a proportion of gastric carcinomas may be explained by LOH and methylation of the TFF1 promoter region. Our results further support the role of TFF1 inactivation in gastric carcinogenesis, in agreement with the results obtained in the Tff1-knockout mice model.
有人提出三叶因子（TFF）1基因是一种候选肿瘤抑制基因，可能参与人类胃癌的发生和/或发展。我们旨在阐明TFF1在胃癌发生中的假定作用。对90例胃癌和8种胃癌衍生细胞系进行TFF1突变筛查；对原发性肿瘤和细胞系的子集进行杂合性缺失（LOH）、免疫组织化学和启动子甲基化分析。在90例胃癌中均未检测到TFF1突变。28例信息充分的病例中有8例（28%）在TFF1位点显示杂合性缺失，免疫组织化学显示TFF1染色缺失。这些结果表明，胃癌中TFF1表达的缺失频繁发生，其机制与突变无关。在不表达的胃癌衍生细胞系和组织中观察到广泛的TFF1启动子甲基化。表达细胞系以及正常胃黏膜启动子甲基化很少或没有。胃癌DNA出现启动子的从头甲基化。这些结果表明启动子甲基化参与了TFF1的关闭。我们得出结论，TFF1点突变在胃癌发生中似乎是罕见事件。一部分胃癌中TFF1表达的缺失可能由TFF1启动子区域的杂合性缺失和甲基化来解释。我们的结果进一步支持了TFF1失活在胃癌发生中的作用，这与在Tff1基因敲除小鼠模型中获得的结果一致。
