DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in glioma
DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in glioma
复制标题
DNA 损伤修复改变调节小胶质细胞的 M2 极化，通过胶质瘤中 p53 介导的 MDK 表达来重塑肿瘤微环境
DOI：
10.1016/j.ebiom.2019.01.067
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发表时间：
2019-03-01
期刊：
影响因子：
11.1
通讯作者：
Cai, Jinquan
中科院分区：
文献类型：
--
作者：
Meng, Xiangqi;Duan, Chunbin;Cai, Jinquan
背景：DNA损伤修复（DDR）改变是癌症发生、进展和治疗耐药的重要事件。然而，DDR改变在胶质瘤恶性肿瘤中的作用需要进一步研究。本研究旨在表征DDR改变的胶质瘤的临床和分子特征，阐明DDR改变调控胶质瘤与肿瘤微环境间串扰的生物学过程。方法：采用综合转录组学和基因组学分析，对DDR改变在胶质瘤中的作用进行全面调查。从多个数据集中确定与预后相关的ddr细胞因子。体内和体外实验验证了DDR关键分子p53在胶质瘤中调节小胶质细胞M2极化的作用。结果：DDR改变与胶质瘤的临床和分子特征有关。DDR改变的胶质瘤表现出不同的免疫表型、免疫细胞类型和细胞因子过程。DDR相关细胞因子对GBM患者的预后不利，并与DDR改变协同作用。DDR通路的关键转录因子p53介导MDK过表达，通过促进小胶质细胞M2极化，重塑GBM免疫抑制微环境，提示DDR可能在调节胶质瘤微环境中发挥潜在作用。解释：我们的研究表明，DDR的改变通过调节免疫反应和细胞因子通路，显著地促进了胶质瘤微环境的重塑。(c) 2019年作者。Elsevier B.V.出版
Background: DNA damage repair (DDR) alterations are important events in cancer initiation, progression, and therapeutic resistance. However, the involvement of DDR alterations in glioma malignancy needs further investigation. This study aims to characterize the clinical and molecular features of gliomas with DDR alterations and elucidate the biological process of DDR alterations that regulate the cross talk between gliomas and the tumor microenvironment.Methods: Integrated transcriptomic and genomic analyses were undertaken to conduct a comprehensive investigation of the role of DDR alterations in glioma. The prognostic DDR-related cytokines were identified from multiple datasets. In vivo and in vitro experiments validated the role of p53, the key molecule of DDR, regulating M2 polarization of microglia in glioma.Findings: DDR alterations are associated with clinical and molecular characteristics of glioma. Gliomas with DDR alterations exhibit distinct immune phenotypes, and immune cell types and cytokine processes. DDR-related cytokines have an unfavorable prognostic implication for GBM patients and are synergistic with DDR alterations. Overexpression of MDK mediated by p53, the key transcriptional factor in DDR pathways, remodels the GBM immunosuppressive microenvironment by promoting M2 polarization of microglia, suggesting a potential role of DDR in regulating the glioma microenvironment.Interpretation: Our work suggests that DDR alterations significantly contribute to remodeling the glioma microenvironment via regulating the immune response and cytokine pathways. (c) 2019 The Authors. Published by Elsevier B.V.