Loss of imprinting and allelic switching at the DLK1-MEG3 locus in human hepatocellular carcinoma.
Loss of imprinting and allelic switching at the DLK1-MEG3 locus in human hepatocellular carcinoma.
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DOI：
10.1371/journal.pone.0049462
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lehmann U
中科院分区：
文献类型：
--
作者：
Anwar SL;Krech T;Hasemeier B;Schipper E;Schweitzer N;Vogel A;Kreipe H;Lehmann U
印记基因的失调是导致人类癌症发展的重要分子机制。然而，在人类肝细胞癌（HCC），世界范围内的第三大癌症死亡原因，印迹缺陷的知识仍然有限。因此，启动了对223个印迹基因座在人HCC中表达的系统性荟萃分析。该筛选揭示了DLK 1-MEG 3基因座在HCC中经常失调。DLK 1和MEG 3表达的失调伴随着DNA甲基化的广泛畸变，可以在超过80%的病例中在一个独立的人HCC系列（n = 40）中通过实验证实。 在HCC中DLK 1-MEG 3基因座的甲基化缺失与DNA甲基化的整体缺失线性相关（r2 = 0.63，p<0.0001）。 使用siRNA抑制HCC细胞中的DNMT 1导致MEG 3-DMR甲基化减少和MEG 3 RNA表达的伴随增加。等位基因特异性表达分析确定了31个信息样本中的10个（32%）印迹缺失，使其成为人类HCC中最常见的分子缺陷之一。在2例病例中，可以证明双等位基因表达的明确获得伴随着IG-DMR处甲基化的实质性丧失。在8例肿瘤细胞显示等位基因转换的单等位基因表达的正常印记等位基因。等位基因转换伴随着主要在IG-DMR 1处的DNA甲基化的获得或丧失。对10例肝细胞腺瘤（HCA）和5例局灶性结节性增生（FNH）的分析证实，这种表观遗传不稳定性与恶性转化过程特异性相关，而与增殖本身无关。必须考虑人类HCC中这种广泛的印记不稳定性，以最大限度地减少靶向DNA甲基化机制的治疗方法的不良副作用。它也可能在未来作为预测性生物标志物和监测表观遗传治疗的反应。
Deregulation of imprinted genes is an important molecular mechanism contributing to the development of cancer in humans. However, knowledge about imprinting defects in human hepatocellular carcinoma (HCC), the third leading cause of cancer mortality worldwide, is still limited. Therefore, a systematic meta-analysis of the expression of 223 imprinted loci in human HCC was initiated. This screen revealed that the DLK1-MEG3 locus is frequently deregulated in HCC. Deregulation of DLK1 and MEG3 expression accompanied by extensive aberrations in DNA methylation could be confirmed experimentally in an independent series of human HCC (n = 40) in more than 80% of cases. Loss of methylation at the DLK1-MEG3 locus correlates linearly with global loss of DNA methylation in HCC (r2 = 0.63, p<0.0001). Inhibition of DNMT1 in HCC cells using siRNA led to a reduction in MEG3-DMR methylation and concomitant increase in MEG3 RNA expression. Allele-specific expression analysis identified loss of imprinting in 10 out of 31 informative samples (32%), rendering it one of the most frequent molecular defects in human HCC. In 2 cases unequivocal gain of bi-allelic expression accompanied by substantial loss of methylation at the IG-DMR could be demonstrated. In 8 cases the tumour cells displayed allelic switching by mono-allelic expression of the normally imprinted allele. Allelic switching was accompanied by gains or losses of DNA methylation primarily at IG-DMR1. Analysis of 10 hepatocellular adenomas (HCA) and 5 cases of focal nodular hyperplasia (FNH) confirmed that this epigenetic instability is specifically associated with the process of malignant transformation and not linked to increased proliferation per se. This widespread imprint instability in human HCC has to be considered in order to minimize unwanted side-effects of therapeutic approaches targeting the DNA methylation machinery. It might also serve in the future as predictive biomarker and for monitoring response to epigenetic therapy.
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影响因子：
8
作者：
Braconi, C.;Kogure, T.;Valeri, N.;Huang, N.;Nuovo, G.;Costinean, S.;Negrini, M.;Miotto, E.;Croce, C. M.;Patel, T.
通讯作者：
Patel, T.
通过RNA-Seq对印迹基因表达的批判性评估：一种新的观点。
影响因子：
4.5
作者：
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通讯作者：
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影响因子：
4
作者：
Engel, JR;Smallwood, A;Maher, ER
通讯作者：
Maher, ER
影响因子：
5
作者：
Lehmann, U;Hasemeier, B;Kreipe, H
通讯作者：
Kreipe, H
影响因子：
7.3
作者：
Poirier, K;Chalas, C;Terris, B
通讯作者：
Terris, B