Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer
Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer
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DOI：
10.1002/ijc.23849
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发表时间：
2009-01-01
影响因子：
6.4
通讯作者：
Liloglou, Triantafillos
中科院分区：
文献类型：
--
作者：
Daskalos, Alexandros;Nikolaidis, Georgios;Liloglou, Triantafillos
LINE-1和Alu元件是非LTR反转录转座子，共同构成超过3010个人类真基因，并且它们在人类肿瘤中经常低甲基化。全球低甲基化和基因组不稳定性之间的关系已被证明，然而，很少有证据表明低甲基化介导的逆转录因子在人类癌症中的激活作用。在我们的研究中，我们用焦磷酸测序法检测了48例原发性非小细胞癌及其配对的癌旁组织中LINE-1和Alu序列的甲基化水平。我们证明了两种元素的甲基化水平显著降低（分别为p = 7.7 x 10（-14）和9.6 x 10（-7））。2个元件的甲基化指数相关（p = 0.006），表明它们的甲基化维持可能存在共同机制。利用位于肺癌热点区域如3 p、5 q、9 p、13 q和17 p的11个荧光微卫星标记来测量基因组不稳定性。两种转座因子的低甲基化与基因组不稳定性增加相关（LINE，p = 7.1 × 10（-5）; Alu，p = 0.008）。在用5-氮杂-2 '-脱氧胞苷处理3个肺细胞系后，LINE-1和Alu的甲基化指数的降低一致地导致两种元素的表达增加。我们的研究证明了转座因子低甲基化与非小细胞肺癌基因组不稳定性之间的密切联系，并为这些因子在肺肿瘤中的潜在积极作用提供了早期证据。由于去甲基化剂现在进入肺癌试验，为了推进表观遗传学在癌症治疗中的临床应用，必须更深入地了解沉默逆转录转座子的潜在再激活。(C)2008 Wiley-Liss，Inc.
LINE-1 and Alu elements are non-LTR retrotransposons, constituting together over 3010 of the human genuine and they are frequently hypomethylated in human tumors. A relationship between global hypomethylation and genomic instability has been shown, however, there is little evidence to suggest active role for hypomethylation-mediated reactivation of retroelements in human cancer. In our study, we examined by Pyrosequencing the methylation levels of LINE-1 and Alu sequences in 48 primary nonsmall cell carcinomas and their paired adjacent tissues. We demonstrate a significant reduction of the methylation levels of both elements (p = 7.7 x 10(-14) and 9.6 x 10(-7), respectively). The methylation indices of the 2 elements correlated (p = 0.006), suggesting a possible common mechanism for their methylation maintenance. Genomic instability was measured utilizing 11 fluorescent microsatellite markers located on lung cancer hot-spot regions such as 3p, 5q 9p, 13q and 17p. Hypomethylation of both transposable elements was associated with increased genomic instability (LINE, p = 7.1 x 10(-5); Alu, p = 0.008). The reduction of the methylation index of LINE-1 and Alu following treatment of 3 lung cell lines with 5-aza-2'-deoxycitidine, consistently resulted in increased expression of both elements. Our study demonstrates the strong link between hypomethylation of transposable elements with genomic instability in non-small cell lung cancer and provides early evidence for a potential active role of these elements in lung neoplasia. As demethylating agents are now entering lung cancer trials, it is imperative to gain a greater insight into the potential reactivation of silent retrotransposons in order to advance for file clinical utilization of epigenetics in cancer therapy. (C) 2008 Wiley-Liss, Inc.