title: The role and regulatory mechanism of IL-1β on the methylation of the NF2 gene in benign meningiomas and leptomeninges.
abstract: 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-1β, 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-1β occurred in a dose- and time-dependent manner. Methylation-specific PCR verified that IL-1β 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-1β 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-1β 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-κB pathways. These results suggest that IL-1β induces methylation of NF2 by up-regulating DNMT1 in benign meningioma cells and DNMT1/3b in leptomeningeal cells via MAPK and NF-κB pathways. Therefore, NF2 methylation is a linker between IL-1β and tumor development, and DNMTs might be potential therapeutic targets in meningioma for regulating NF2 and inhibiting tumor development. © 2016 Wiley Periodicals, Inc.
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Baofeng
authors: B
authors: Wang
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Zhenwen
authors: Z
authors: Cui
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Zhihong
authors: Z
authors: Zhong
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Yuhao
authors: Y
authors: Sun
authors: Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.|Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Guo-Yuan
authors: GY
authors: Yang
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Department of Neurosurgery, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Qingfang
authors: Q
authors: Sun
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Liuguan
authors: L
authors: Bian
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology*; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000276:immunology; D008579:Meningioma / Q000235:genetics* / Q000276:immunology; D016518:Neurofibromatosis 2 / Q000235:genetics*; D025581:Neurofibromin 2 / Q000235:genetics; D011401:Promoter Regions, Genetic; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
chemical_list: D053583:Interleukin-1beta; D025581:Neurofibromin 2; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619382:Dnmt1 protein, rat
keywords: DNA methyltransferase; IL-1β; NF2; leptomeninges; meningioma