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EZH2 抑制在胶质母细胞瘤中使肿瘤微环境中的小胶质细胞向 M1 表型转移。

EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment.

机构信息

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yangjiang Xi Road 107, Guangzhou, China.

Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

出版信息

J Neuroinflammation. 2017 Nov 13;14(1):220. doi: 10.1186/s12974-017-0993-4.

Abstract

BACKGROUND

Glioblastoma multiforme (GBM) induces tumor immunosuppression through interacting with tumor-infiltrating microglia or macrophages (TAMs) with an unclear pathogenesis. Enhancer of zeste homolog 2 (EZH2) is abundant in GBM samples and cell lines and is involved in GBM proliferation, cell cycle, and invasion, whereas its association with innate immune response is not yet reported. Herein, the aim of this study was to investigate the role of EZH2 in GBM immune.

METHODS

Co-culturing models of human/murine GBM cells with PBMC-derived macrophages/primary microglia were employed. EZH2 mRNAs and function were suppressed by siEZH2 and DZNep. Real-time PCR and flow cytometry were used to determine levels of microglia/macrophages markers. The fluorescence-labeled latex beads and flow cytometry were utilized to evaluate phagocytic abilities of microglia. CCK8 assay was performed to assess microglia proliferation.

RESULTS

EZH2 inhibition led to significant reduction of TGFβ1-3 and IL10 and elevation of IL1β and IL6 in human and murine GBM cells. More importantly, EZH2 suppression in GBM cells resulted in significant increase of M1 markers (TNFα and iNOS) and decrease of a pool of M2 markers in murine microglia. The proportion of CD206 cells was decreased in PBMC-derived macrophages as co-incubated with EZH2-inhibited GBM cells. Functional researches showed that phagocytic capacities of microglia were significantly ameliorated after EZH2 inhibition in co-culturing GBM cells and microglia proliferation was declined after addition of TGFβ2 antibodies to co-incubated GBM cells with EZH2 inhibition. Besides, we found that EZH2 suppression in GBM cells enhanced co-culturing microglia engulfment through activation of iNOS.

CONCLUSIONS

Our data demonstrates that EZH2 participates in GBM-induced immune deficient and EZH2 suppression in GBM can remodel microglia immune functions, which is beneficial for understanding GBM pathogenesis and suggests potential targets for therapeutic approaches.

摘要

背景

多形性胶质母细胞瘤(GBM)通过与肿瘤浸润性小胶质细胞或巨噬细胞(TAMs)相互作用诱导肿瘤免疫抑制,但发病机制尚不清楚。EZH2 在 GBM 样本和细胞系中含量丰富,参与 GBM 的增殖、细胞周期和侵袭,但其与固有免疫反应的关系尚未报道。本研究旨在探讨 EZH2 在 GBM 免疫中的作用。

方法

采用人/鼠 GBM 细胞与 PBMC 来源的巨噬细胞/原代小胶质细胞共培养模型。用 siEZH2 和 DZNep 抑制 EZH2 mRNA 和功能。实时 PCR 和流式细胞术用于检测小胶质细胞/巨噬细胞标志物的水平。荧光标记的乳胶珠和流式细胞术用于评估小胶质细胞的吞噬能力。CCK8 法评估小胶质细胞增殖。

结果

EZH2 抑制导致人源和鼠源 GBM 细胞中 TGFβ1-3 和 IL10 水平显著降低,IL1β 和 IL6 水平显著升高。更重要的是,EZH2 抑制 GBM 细胞后,鼠源小胶质细胞中 M1 标志物(TNFα 和 iNOS)显著增加,M2 标志物减少。与 EZH2 抑制的 GBM 细胞共孵育的 PBMC 来源的巨噬细胞中 CD206 细胞的比例降低。在 EZH2 抑制的 GBM 细胞与小胶质细胞共培养中加入 TGFβ2 抗体后,小胶质细胞的吞噬能力显著改善,EZH2 抑制的 GBM 细胞共培养中小胶质细胞增殖下降。此外,我们发现 EZH2 抑制 GBM 细胞通过激活 iNOS 增强共培养小胶质细胞吞噬作用。

结论

我们的数据表明,EZH2 参与 GBM 诱导的免疫缺陷,EZH2 抑制 GBM 可重塑小胶质细胞免疫功能,有助于理解 GBM 发病机制,并提示治疗方法的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b2c/5684749/14ec4fa93199/12974_2017_993_Fig1_HTML.jpg

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