Cho Yong Gu, Song Jae Hwi, Kim Chang Jae, Nam Suk Woo, Yoo Nam Jin, Lee Jung Young, Park Won Sang
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
APMIS. 2007 Jul;115(7):802-8. doi: 10.1111/j.1600-0463.2007.apm_643.x.
KLF4, which is also known as the gut-enriched Kruppel-like factor, plays important roles during the proliferation and differentiation of gastrointestinal epithelial cells. A loss of KLF4 expression has been observed in human tumors, particularly in the gastrointestinal tract. In this study, the molecular basis of the KLF4 inactivation in gastric cancer was investigated by analyzing the somatic mutation, the allelic loss with two microsatellite markers, D9S53 and D9S105, and hypermethylation of the KLF4 gene in 47 gastric adenomas and 81 gastric adenocarcinomas. Mutational analysis revealed one mutation of the KLF4 gene in a diffuse-type advanced gastric adenocarcinoma, but not in the gastric adenoma. This mutation was a somatic missense mutation, GGG-->AGG (Gly-->Arg) at codon 107 in exon 3, which encodes a transcriptional activation domain of the protein. An allelic loss was found in 7 (22.6%) of the 31 informative gastric adenoma cases and 15 (31.3%) of the 48 informative cancer cases at one or both markers. In addition, promoter hypermethylation of the KLF4 gene was observed in only two gastric cancers. These results suggest that genetic and epigenetic alterations of the KLF4 gene might play a minor role in gastric carcinogenesis.
KLF4，也被称为肠道富集型Kruppel样因子，在胃肠道上皮细胞的增殖和分化过程中发挥着重要作用。在人类肿瘤中，尤其是胃肠道肿瘤中，已观察到KLF4表达缺失。在本研究中，通过分析47例胃腺瘤和81例胃腺癌中KLF4基因的体细胞突变、两个微卫星标记D9S53和D9S105的等位基因缺失以及KLF4基因的高甲基化，研究了胃癌中KLF4失活的分子基础。突变分析显示，在一例弥漫型晚期胃腺癌中发现了KLF4基因的一个突变，但在胃腺瘤中未发现。该突变是一个体细胞错义突变，位于外显子3的第107密码子处，GGG→AGG（甘氨酸→精氨酸），该密码子编码该蛋白的转录激活结构域。在31例信息充分的胃腺瘤病例中有7例（22.6%）以及48例信息充分的癌症病例中有15例（31.3%）在一个或两个标记处发现等位基因缺失。此外，仅在两例胃癌中观察到KLF4基因的启动子高甲基化。这些结果表明，KLF4基因的遗传和表观遗传改变在胃癌发生过程中可能起次要作用。
