Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers.
Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers.
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DOI：
10.3892/ijo.31.1.169
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发表时间：
2007-07
影响因子：
5.2
通讯作者：
K. Kaira;N. Sunaga;Y. Tomizawa;N. Yanagitani;T. Ishizuka;R. Saito;T. Nakajima;M. Mori
中科院分区：
文献类型：
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作者：
K. Kaira;N. Sunaga;Y. Tomizawa;N. Yanagitani;T. Ishizuka;R. Saito;T. Nakajima;M. Mori
RASSF 2是RAS相关结构域家族1（RASSF 1）的成员，是一个候选的肿瘤抑制基因（TSG），在几种人类癌症中通过启动子超甲基化而沉默。在这项研究中，我们研究了RASSF 2 mRNA的表达和启动子甲基化状态在肺癌细胞株和106例原发性非小细胞肺癌（NSCLC）的肿瘤样本中的甲基化特异性PCR。RASSF 2表达在26%的小细胞肺癌（SCLC; n=27株）和50%的NSCLC（n=42株）中不存在。在18%的SCLC细胞系（n=22）和62%的NSCLC细胞系（n=26）中发现RASSF 2启动子甲基化，并且甲基化状态与RASSF 2表达的丧失密切相关。在不表达RASSF 2的NSCLC细胞系中，通过用5-氮杂-2-脱氧胞苷和/或雷帕他汀-A处理来恢复RASSF 2表达。在31%的原发性NSCLC肿瘤中发现了RASSF 2甲基化，非吸烟者标本中甲基化的频率（40例中的18例，45%）高于吸烟者标本（66例中的15例，23%，P=0.014）。我们还研究了RASSF 2甲基化与KRAS和EGFR突变以及RASSF 1A启动子超甲基化的相关性;然而，我们没有发现RASSF 2甲基化与这些遗传和表观遗传变化之间的显著相关性。我们的研究结果表明，RASSF 2基因的异常甲基化与随后的RASSF 2表达的丧失在肺癌的发病机制中起着重要的作用。
RASSF2, a member of the RAS association domain family 1 (RASSF1), is a candidate tumor suppressor gene (TSG) that is silenced by promoter hypermethylation in several human cancers. In this study, we examined the expression of RASSF2 mRNA and the promoter methylation status in lung cancer cell lines and in tumor samples of 106 primary non-small cell lung cancers (NSCLCs) by methylation-specific PCR. RASSF2 expression was absent in 26% of small cell lung cancers (SCLCs; n=27 lines) and 50% of NSCLCs (n=42 lines). Promoter methylation of RASSF2 was found in 18% of the SCLC cell lines (n=22) and 62% of the NSCLC cell lines (n=26), and the methylation status was tightly associated with the loss of RASSF2 expression. RASSF2 expression was restored by treatment with 5-aza-2-deoxycytidine and/or trichostatin-A in the NSCLC cell lines which were absent of the expression. RASSF2 methylation was found in 31% of primary NSCLC tumors, and methylation was more frequent in the specimens from non-smokers (18 of 40, 45%) than in the specimens from smokers (15 of 66, 23%, P=0.014). We also examined the association of RASSF2 methylation with mutations of KRAS and EGFR and with promoter hypermethylation of RASSF1A; however, we could not find a significant association between RASSF2 methylation and these genetic and epigenetic changes. Our results indicate that aberrant methylation of the RASSF2 gene with the subsequent loss of RASSF2 expression plays an important role in the pathogenesis of lung cancers.