The role and regulatory mechanism of IL-1 on the methylation of the NF2 gene in benign meningiomas and leptomeninges
The role and regulatory mechanism of IL-1 on the methylation of the NF2 gene in benign meningiomas and leptomeninges
复制标题
IL-1β对良性脑膜瘤和软脑膜NF2基因甲基化的作用及调控机制
DOI：
10.1002/mc.22467
复制
发表时间：
2016-12-01
影响因子：
4.6
通讯作者：
Bian, Liuguan
中科院分区：
文献类型：
--
作者：
Wang, Baofeng;Cui, Zhenwen;Bian, Liuguan
低级别脑膜瘤（WHO I级）中神经纤维瘤病2型（NF 2）基因的甲基化在肿瘤发生和发展中起着至关重要的作用。脑膜瘤的形成也可能发生在炎症微环境中。然而，炎症与NF 2甲基化之间的关系仍不清楚。本研究旨在探讨IL-1在良性脑膜瘤NF-2甲基化中的作用及其调控机制。培养三个原代低度恶性脑膜瘤细胞和软脑膜细胞。CCK-8和BrdU测定表明，脑膜瘤/软脑膜细胞与IL-1处理的增殖发生在剂量和时间依赖性的方式。甲基化特异性PCR证实IL-1诱导脑膜瘤/软脑膜细胞NF 2启动子甲基化并降低NF 2/merlin表达。实时荧光定量PCR、免疫印迹和免疫荧光检测结果显示，IL-1可上调脑膜瘤细胞中的DNMT 1和软脑膜细胞中的DNMT 1/3b，但不上调DNMT 3a。在用DNMT抑制剂5-氮杂-2-脱氧胞苷和DNMT siRNA共同处理后，IL-1诱导的NF 2甲基化减弱，merlin表达恢复。此外，我们发现脑膜瘤中的DNMT 1和软脑膜中的DNMT 1/3b通过MAPK（p38，ERK，JNK）和NF-B途径的激活来调节。这些结果表明IL-1通过MAPK和NF-B途径上调良性脑膜瘤细胞中的DNMT 1和软脑膜细胞中的DNMT 1/3b来诱导NF 2甲基化。因此，NF 2甲基化是IL-1与肿瘤发生发展之间的一个连接器，DNMT可能是脑膜瘤中调节NF 2和抑制肿瘤发展的潜在治疗靶点。(c)2016 Wiley Periodicals，Inc.
Methylation of the neurofibromatosis type 2 (NF2) gene in low-grade meningioma (WHO grade I) has crucial roles in tumorigenesis and development. Meningioma formation might also occur in the setting of an inflammatory microenvironment. However, the association between inflammation and the methylation of NF2 remains unclear. The present study investigates the role and regulatory mechanism of IL-1, one of the most important pro-inflammatory cytokines, in the methylation of NF2 in benign meningioma. Three primary low-grade meningioma cells and leptomeningeal cells were cultured. CCK-8 and BrdU assays demonstrated that proliferation of meningioma/leptomeningeal cells treated with IL-1 occurred in a dose- and time-dependent manner. Methylation-specific PCR verified that IL-1 induced methylation of the NF2 promoter and decreased NF2/merlin expression in meningioma/leptomeningeal cells. Real-time PCR, western blotting, and immunofluorescence showed that IL-1 up-regulated DNMT1 in meningioma cells and DNMT1/3b in leptomeningeal cells but did not up-regulate DNMT3a. After co-treatment with the DNMT inhibitor 5-Aza-2-deoxycytidine and DNMT siRNA, methylation of NF2 induced by IL-1 was attenuated and merlin expression was restored. Furthermore, we showed that DNMT1 in meningiomas and DNMT1/3b in leptomeninges were regulated via activation of the MAPK (p38, ERK, JNK) and NF-B pathways. These results suggest that IL-1 induces methylation of NF2 by up-regulating DNMT1 in benign meningioma cells and DNMT1/3b in leptomeningeal cells via MAPK and NF-B pathways. Therefore, NF2 methylation is a linker between IL-1 and tumor development, and DNMTs might be potential therapeutic targets in meningioma for regulating NF2 and inhibiting tumor development. (c) 2016 Wiley Periodicals, Inc.