Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer.
Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer.
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DOI：
10.3892/or.15.5.1281
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发表时间：
2006-05
期刊：
影响因子：
4.2
通讯作者：
Hong Chen;Makoto Suzuki;Yohko Nakamura;M. Ohira;S. Ando;T. Iida;T. Nakajima;A. Nakagawara;H. Kimura
中科院分区：
文献类型：
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作者：
Hong Chen;Makoto Suzuki;Yohko Nakamura;M. Ohira;S. Ando;T. Iida;T. Nakajima;A. Nakagawara;H. Kimura
启动子CpG甲基化异常导致肿瘤抑制基因（TSGs）沉默，可能在许多癌症类型的发生中起关键作用。RASSF 1A被认为是TSG，在肺癌和其他恶性肿瘤中已被广泛研究，而RASGRF 2仅被报道可能在胰腺癌细胞系的发病机制中发挥作用。本研究的目的是i）确定RASGRF 2的甲基化谱，ii）比较肺癌中RASGRF 2和RASSF 1A的甲基化谱。我们通过逆转录PCR检测了肺癌细胞系中RASGRF 2的表达，并通过甲基化特异性PCR检测了RASGRF 2的异常甲基化。36%的肺癌细胞系中存在RASGRF 2表达缺失，而30%（3/10）的非小细胞肺癌（NSCLC）细胞系和25%（1/4）的小细胞肺癌（SCLC）细胞系中存在RASGRF 2异常甲基化。RASGRF 2基因表达缺失与异常甲基化的符合率为86%（12/14）。在用去甲基化剂5-氮杂-2 '-脱氧胞苷处理后，在所有四种检测的下调RASGRF 2表达的细胞系中，RASGRF 2表达恢复。在原发性NSCLC中，RASGRF 2和RASSF 1A甲基化分别在34%（39/114）和39%（44/114）的病例中观察到，而在相应的非恶性肺组织中仅观察到7%（4/57）的甲基化。RASGRF 2和RASSF 1A甲基化状态之间没有相关性。RASGRF 2和RASSF 1A甲基化与临床特征无关。RASGRF 2基因在肿瘤细胞中频繁甲基化和沉默可能在NSCLC的发生发展中起着不同于RASSF 1A的重要作用。
Aberrant methylation of promoter CpG that causes silencing of tumor suppressor genes (TSGs) may play a key role in the carcinogenesis of many cancer types. RASSF1A, regarded as a TSG, has been extensively studied in lung cancer and other malignant tumors, whereas RASGRF2 has only been reported to possibly play a role in the pathogenesis of pancreatic cancer cell lines. The aims of our study were to i) determine the methylation profile of RASGRF2 and ii) compare the methylation profiles of RASGRF2 with RASSF1A in lung cancer. We examined RASGRF2 expression by reverse transcription PCR and aberrant methylation of RASGRF2 by methylation-specific PCR in lung cancer cell lines. Loss of RASGRF2 expression was presented in 36% lung cancer cell lines while aberrant methylation of RASGRF2 was present in 30% (3/10) non-small cell lung cancer (NSCLC) cell lines and in 25% (1/4) small cell lung cancer (SCLC) cell lines. The concordance between loss of expression and aberrant methylation of RASGRF2 was 86% (12/14). RASGRF2 expression was restored after treatment with the demethylating agent, 5-aza-2'-deoxycytidine in all four cell lines tested that downregulated RASGRF2 expression. Among primary NSCLC, RASGRF2 and RASSF1A methylation was observed in 34% (39/114) and 39% (44/114) of cases respectively, while it was observed in only 7% (4/57) and none of the corresponding non-malignant lung tissue. There is no correlation between RASGRF2 and RASSF1A methylation status. Both RASGRF2 and RASSF1A methylation did not associate with clinical characteristics. Frequent methylation and silencing of RASGRF2 in tumor cells may play an important role, different from that of RASSF1A, in the carcinogenesis of NSCLC.