Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer
Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer
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DOI：
10.1111/j.1349-7006.2006.00351.x
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发表时间：
2007-01-01
期刊：
影响因子：
5.7
通讯作者：
Tokino, Takashi
中科院分区：
文献类型：
--
作者：
Akino, Kimishige;Toyota, Minoru;Tokino, Takashi
表观遗传基因失活在多种癌症的发生发展中起关键作用。我们利用甲基化CpG岛扩增结合代表性差异分析来鉴定胃癌中因DNA甲基化而失活的基因，确定了7个与受影响基因的5' CpG岛相对应的DNA片段。回收的其中一个克隆与DFNA5的5'侧翼区域相同，DFNA5是一个先前已表明与耳聋有关且由DNA损伤诱导的基因。进一步分析显示，DFNA5在正常组织中表达，但在胃癌细胞系中由于其转录起始位点周围区域的甲基化而下调。用甲基转移酶抑制剂5 - 氮杂 - 2' - 脱氧胞苷处理缺乏DFNA5表达的胃癌细胞，可恢复该基因的表达。在50%的原发性胃癌肿瘤中检测到DFNA5甲基化，且与爱泼斯坦 - 巴尔病毒阳性和无转移相关。此外，将外源性DFNA5导入沉默细胞可抑制集落形成。综上所述，这些数据表明DFNA5的沉默在胃癌中频繁发生，并可能在该疾病的发生和发展中起关键作用。
Epigenetic gene inactivation plays a key role in the development of various types of cancer. Using methylated CpG island amplification coupled with representational difference analysis to identify genes inactivated by DNA methylation in gastric cancer, we identified seven DNA fragments corresponding to the 5' CpG islands of the affected genes. One of the clones recovered was identical to the 5' flanking region of DFNA5, a gene previously shown to be associated with deafness and induced by DNA damage. Further analysis revealed that DFNA5 is expressed in normal tissues but is downregulated in gastric cancer cell lines due to methylation of the region around its transcription start site. Treating gastric cancer cells that lacked DFNA5 expression with a methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the gene's expression. Methylation of DFNA5 was detected in 50% of primary gastric tumors, and was correlated with positivity for Epstein-Barr virus and the absence of metastasis. Moreover, introduction of exogenous DFNA5 into silenced cells suppressed colony formation. Taken together, these data suggest that the silencing of DFNA5 occurs frequently in gastric cancer and may play a key role in development and progression of the disease.