Epigenetic Regulation of ANKRD18B in Lung Cancer
Epigenetic Regulation of ANKRD18B in Lung Cancer
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ANKRD18B 在肺癌中的表观遗传调控
DOI：
10.1002/mc.22101
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发表时间：
2015-04-01
影响因子：
4.6
通讯作者：
Liu, Jin-Yi
中科院分区：
文献类型：
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作者：
Liu, Wen-Bin;Han, Fei;Liu, Jin-Yi
识别肺癌发生的关键遗传和表观遗传变化将有助于肺癌的有效早期诊断和靶向治疗。本研究筛选了一个新的高甲基化基因锚蛋白重复结构域18 B（ANKRD 18 B），以确定其是否受DNA甲基化的调控，并阐明其在肺癌中的生物学和临床意义。通过甲基化特异性PCR、亚硫酸氢盐基因组测序和定量逆转录聚合酶链反应（qRT-PCR）分析甲基化状态和表达水平。我们在98例原发性肺癌组织中的52例（53.1%）和10例细胞系中的9例（90%）中检测到ANKRD 18 B超甲基化，而在10例正常肺组织样本中未观察到甲基化。ANKRD 18 B甲基化在分化差的胃癌中更常见（P < 0.05）。值得注意的是，来自肿瘤组织显示ANKRD 18 B高甲基化的患者的62对样品分别在其相应的血浆和痰样品的72.7%和69.7%中表现出相同的异常甲基化;而在肿瘤样品缺乏这种改变的患者的痰和血浆中没有检测到ANKRD 18 B的高甲基化。此外，ANKRD 18 B mRNA表达在肺癌组织和与ANKRD 18 B区域高甲基化相关的细胞系中显著降低或沉默。去甲基化剂5-氮-2 ′-脱氧胞苷显著增加肺癌细胞株ANKRD 18 B mRNA的表达。此外，ANKRD 18 B的过表达抑制肺癌细胞生长。这些结果提示ANKRD 18 B在肺癌中的表达受CpG岛高甲基化的调控。我们的研究结果证实了鉴定癌症表观遗传失调的新标志物的重要性。© 2013 Wiley Periodicals，Inc.
The identification of the key genetic and epigenetic changes underlying lung carcinogenesis would aid effective early diagnosis and targeted therapies for lung cancer. In this study, we screened a novel hypermethylated gene ankyrin repeat domain 18B (ANKRD18B), to determine whether it is regulated by DNA methylation and clarify its biological and clinical implications in lung cancer. Methylation status and expression level were analyzed by methylation‐specific PCR, bisulfite genomic sequencing, and quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR). We detected ANKRD18B hypermethylation in 52 of 98 (53.1%) primary lung cancer tissues and in nine of 10 (90%) cell lines, whereas no methylation was seen in 10 normal lung tissue samples. ANKRD18B methylation was more frequently observed in patients with poor differentiation (P < 0.05). Notably, 62 pairs of samples from patients whose tumor tissue showed hypermethylation of ANKRD18B exhibited the same aberrant methylation in 72.7% and 69.7% of their corresponding plasma and sputum samples, respectively; whereas no hypermethylation of ANKRD18B was detected in the sputum and plasma from patients whose tumor sample lacked this alteration. In addition, ANKRD18B mRNA expression was significantly decreased or silenced in lung cancer tissues and cell lines associated with hypermethylation of the ANKRD18B region. Demethylation agent 5‐aza‐2′‐deoxycytidine significantly increased ANKRD18B mRNA expression in lung cancer cell lines. Furthermore, overexpression of ANKRD18B suppressed lung cancer cell growth. These results suggest that the expression of ANKRD18B is regulated by CpG island hypermethylation in lung cancer. Our findings confirm the importance of the identification of new markers of epigenetic dysregulation in cancer. © 2013 Wiley Periodicals, Inc.