miR-142-3p 对 M2 巨噬细胞的影响及其对小鼠脑胶质母细胞瘤的治疗效果。
Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma.
机构信息
Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
出版信息
J Natl Cancer Inst. 2014 Jun 28;106(8). doi: 10.1093/jnci/dju162. Print 2014 Aug.
BACKGROUND
The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.
METHODS
An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided.
RESULTS
miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R (2) = .303).
CONCLUSIONS
These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.
背景
微 RNA（miRNA）在肿瘤介导的免疫抑制背景下的免疫治疗潜力，以前尚未在单核细胞衍生的神经胶质瘤相关巨噬细胞中描述过，这些巨噬细胞是神经胶质瘤中最大的浸润免疫细胞群，并促进神经胶质瘤的发生。
方法
采用 miRNA 微阵列比较人类神经胶质瘤浸润巨噬细胞与匹配的外周单核细胞的表达谱。确定 miR-142-3p 对促炎 M1 和免疫抑制 M2 巨噬细胞表型和功能的影响。在携带脑内 GL261 神经胶质瘤的免疫功能正常的 C57BL/6J 小鼠和携带高级别神经胶质瘤的基因工程 Ntv-a 小鼠中确定 miR-142-3p 的治疗效果。采用 Student t 检验评估体外数据集之间的差异。采用对数秩检验分析生存情况，采用线性混合模型和 F 检验分析肿瘤大小。所有统计检验均为双侧检验。
结果
miR-142-3p 是神经胶质瘤浸润巨噬细胞中下调最明显的 miRNA（约 4.95 倍）。M2 巨噬细胞的 miR-142-3p 表达低于 M1 巨噬细胞（P =.03）。M2 巨噬细胞中 miR-142-3p 的过表达诱导转化生长因子-β受体 1 的选择性调节，导致随后 M2 亚群的选择性凋亡（P =.01）。体内给予 miR-142-3p 可抑制神经胶质瘤生长（P =.03，n = 5）并延长中位生存期（miR-142-3p 治疗的 C57BL/6J 小鼠与对照 scramble：31 天与 23.5 天，P =.03，n = 10；miR-142-3p 治疗的 Ntv-a 小鼠与对照 scramble：32 天与 24 天，P =.03，n = 9），同时浸润的巨噬细胞减少（R（2）=.303）。
结论
这些数据表明，miR-142-3p 通过转化生长因子-β信号通路调节 M2 巨噬细胞，在神经胶质瘤免疫中发挥独特作用。
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