Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma
Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma
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DOI：
10.1002/ijc.22185
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发表时间：
2007-01-01
影响因子：
6.4
通讯作者：
Huang, Guangwu
中科院分区：
文献类型：
--
作者：
Zhang, Zhe;Sun, Di;Huang, Guangwu
RASSF2可直接与K-RAS结合，对RAS蛋白起负效应作用。RASSF2A是RASSF2的唯一一个在其启动子中含有CpG岛的亚型，已有报道在几种人类癌症中其启动子甲基化使其失活。本研究旨在探讨鼻咽癌组织中RASSF2A的表达与其启动子甲基化的关系。RASSF2A在80%(4/5)的鼻咽癌细胞系中表达下调。与正常鼻咽上皮相比，鼻咽癌组织中RASSF2A的表达也降低。RASSF2A基因启动子甲基化在所有鼻咽癌细胞系(4/5)和50.9%(27/53)的鼻咽癌细胞中均可检测到，而在所有正常鼻咽癌组织中均未检测到。RASSF2A甲基化病例的RASSF2A表达水平显著低于未甲基化病例。甲基转移酶抑制剂5-aza-DC可显著恢复鼻咽癌细胞株RASSF2A的表达。此外，RASSF2A甲基化患者的淋巴结转移率较高(p<；0.05)。RASSF2A在RASSF2A沉默和甲基化的鼻咽癌细胞株CNE2中的异位表达表明，RASSF2A可以抑制细胞周期进展、克隆形成和细胞迁移，这进一步证明RASSF2A是一个候选的肿瘤抑制基因。综上所述，候选抑癌基因RASSF2A经常被其启动子甲基化失活，这种异常甲基化与鼻咽癌的淋巴转移有关。(C)2006年Wiley-Liss，Inc.
RASSF2 can bind directly to K-Ras and function as a negative effector of Ras protein. RASSF2A is the only isoform of RASSF2 that contains CpG islands in its promoter and it has been reported to be inactivated by its promoter methylation in several human cancers. In the present study, we investigated the correlation of RASSF2A expression with its promoter methylation in nasopharyngeal carcinoma (NPC). Expression of RASSF2A was down-regulated in 80% (4/5) of NPC cell lines. Decreased RASSF2A expression was also observed in NPC primary tumors compared with normal nasopharyngeal epithelia. Promoter methylation of RASSF2A could be detected in all the RASSF2A-silenced cell lines (4/5) of the NPC cell lines and 50.9% (27/53) of primary tumors, but not in any of the normal epithelia. RASSF2A-methylated cases showed a significantly lower level of RASSF2A expression than unmethylated cases. Loss of RASSF2A expression can be greatly restored by the methyltransferase inhibitor 5-aza-dC in NPC cell lines. In addition, patients with methylated RASSF2A presented a higher frequency of lymph node metastasis (p < 0.05). Ectopic expression of RASSF2A in RASSF2A-silenced and -methylated NPC cell line CNE2 shows that RASSF2A could inhibit cell cycle progression, colony formation and cell migration, which provided further evidence that RASSF2A is a candidate tumor suppressor gene. In conclusion, RASSF2A, a candidate tumor suppressor gene (TSG), is frequently inactivated by its promoter methylation and this aberrant methylation correlates with lymph node metastasis in NPC. (c) 2006 Wiley-Liss, Inc.