Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays
Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays
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DOI：
10.1158/0008-5472.can-04-3340
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发表时间：
2005-03-15
期刊：
影响因子：
11.2
通讯作者：
Sasaki, H
中科院分区：
文献类型：
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作者：
Nishigaki, M;Aoyagi, K;Sasaki, H
虽然低甲基化是最初确定的癌症表观遗传变化，但多年来它被忽视，而不是高甲基化。最近，癌症相关的低甲基化基因激活被重新发现。然而，在胃癌中，尚未发现全基因组范围内筛选激活基因的方法。通过使用微阵列，我们在8个胃癌细胞系中至少一个细胞系中鉴定了1，383个候选基因，这些候选基因在5-氮杂-2 '脱氧胞苷和阿司他丁A处理后重新激活。在1,383个基因中，进一步选择了159个基因，包括癌基因ELK 1、FRAT 2、R-RAS、RHOB和RH 06，作为在正常胃粘膜中被DNA甲基化沉默但在胃癌亚组中被DNA去甲基化激活的候选基因。接下来，我们发现R-RAS第一内含子内特定CpG位点的去甲基化导致超过一半的胃癌激活。将siRNA引入表达R-RAS的细胞中导致粘附细胞的消失，这表明功能性阻断R-RAS信号通路对胃癌治疗具有巨大潜力。我们广泛的基因列表提供了这类癌基因的其他候选者。
Although hypomethylation was the originally identified epigenetic change in cancer, it was overlooked for many years in preference to hypermethylation. Recently, gene activation by cancer-linked hypomethylation has been rediscovered. However, in gastric cancer, genome-wide screening of the activated genes has not been found. By using microarrays, we identified 1,383 gene candidates reactivated in at least one cell line of eight gastric cancer cell lines after treatment with 5-aza-2' deoxycytidine and trichostatin A. Of the 1,383 genes, 159 genes, including oncogenes ELK1, FRAT2, R-RAS, RHOB, and RH06, were further selected as gene candidates that are silenced by DNA methylation in normal stomach mucosa but are activated by DNA demethylation in a subset of gastric cancers. Next, we showed that demethylation of specific CpG sites within the first intron of R-RAS causes activation in more than half of gastric cancers. Introduction of siRNA into R-RAS-expressing cells resulted in the disappearance of the adhered cells, suggesting that functional blocking of the R-RAS-signaling pathway has great potential for gastric cancer therapy. Our extensive gene list provides other candidates for this class of oncogene.