Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma
Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma
复制标题
DOI：
10.1111/j.1349-7006.2008.00769.x
复制
发表时间：
2008-05-01
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：
Imai, Takashi;Toyota, Minoru;Tokino, Takashi
肿瘤抑制基因的遗传和表观遗传改变在人类肿瘤发生中起着重要作用。RAS信号在口腔鳞状细胞癌(OSCC)中经常被激活，尽管在日本OSCC患者中很少检测到RAS突变，而且该基因激活的机制尚不清楚。在这里，我们检测了一组口腔鳞癌细胞系中RAS相关家族(RASSF)基因的表达，发现RASSF2在口腔鳞癌细胞中经常被DNA甲基化下调。此外，在46例口腔鳞癌中有12例(26%)检测到RASSF2的异常甲基化，其中18例(39%)至少有一个RASSF基因甲基化。RASSF2在口腔鳞癌细胞中的异位表达可抑制细胞生长并诱导细胞凋亡。缺失RAS结合结构域的RASSF2突变体不能与RAS相互作用，其促凋亡活性低于全长蛋白，表明RASSF2的促凋亡活性与其与RAS的结合有关。对RASSF2调控基因的基因组筛选表明，参与免疫反应、血管生成和转移的基因都受到RASSF2的抑制。我们的结果提示，RASSF2的表观失活在口腔鳞癌的发生发展中起着重要作用，RASSF2可能成为口腔鳞癌诊断和治疗的分子靶点。
Genetic and epigenetic alterations in tumor-suppressor genes play important roles in human neoplasia. Ras signaling is often activated in oral squamous cell carcinoma (OSCC), although Ras mutations are rarely detected in Japanese OSCC patients, and the mechanisms underlying the gene's activation remain unclear. Here, we examined the expression of Ras association family (RASSF) genes in a panel of OSCC cell lines and found that RASSF2 is often downregulated by DNA methylation in OSCC cells. In addition, aberrant methylation of RASSF2 was detected in 12 of 46 (26%) primary OSCC, and 18 (39%) of those OSCC showed methylation of at least one RASSF gene. Ectopic expression of RASSF2 in OSCC cells suppressed cell growth and induced apoptosis. A RASSF2 deletion mutant lacking the Ras-association domain, which was therefore unable to interact with Ras, exhibited less pro-apoptotic activity than the full-length protein, indicating that the pro-apoptotic activity of RASSF2 is related to its association with Ras. Genomic screening of genes regulated by RASSF2 showed that genes involved in immune responses, angiogenesis, and metastasis are suppressed by RASSF2. Our results suggest that epigenetic inactivation of RASSF2 plays an important role in OSCC tumorigenesis, and that RASSF2 may be a useful molecular target for the diagnosis and treatment of OSCC.