miR-7e-5p 下调通过上调 M1 巨噬细胞中的 FasL 来调节免疫抑制性基质，从而促进低级别滤泡性淋巴瘤向侵袭性淋巴瘤的转化。
MiR-7e-5p downregulation promotes transformation of low-grade follicular lymphoma to aggressive lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages.
机构信息
Department of Pathology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, 215123, China.
Department of Pathology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
出版信息
J Exp Clin Cancer Res. 2020 Nov 9;39(1):237. doi: 10.1186/s13046-020-01747-z.
BACKGROUND
In follicular lymphoma (FL), histologic transformation to high-grade FL and diffuse large B-cell lymphoma (DLBCL) is a critical adverse step in disease progression. Activation of the oncogene c-MYC and tumor microenvironment remodeling account for FL progression. A panel of microRNA (miRNA) was downregulated in transformed FL (tFL).
METHODS
Differentially expressed miRNAs were systematically compared in 11 lymph nodes from patients at different stages of disease. Expression of miR-7e-5p was analyzed in 46 B-cell lymphomas, including 30 FL tissues and 16 DLBCL tissues. In FL cells, transcriptional regulation of the oncogene c-MYC on its target miR-7e-5p was revealed by Chromatin Immunoprecipitation (ChIP) assay. Exosome, carrying differentially expressed miR-7e-5p was isolated and visualized by transmission electron microscope and fluorescence tracing. The effect of miR-7e-5p on recipient macrophage was determined by target gene quantification, flow cytometry, and TUNEL method in a cocultured system with miR-7e-5p-mimics or inhibitors treatment. Expression of miR-7e-5p targets, macrophage proportions, and clinical parameters were included for correlation analysis.
RESULTS
We determined that downregulation of miR-7e-5p, driven by c-MYC overexpression, was associated with poorer prognosis in FL patients. The decreased expression of miR-7e-5p in lymphoma cells led to a reduced exosomal transfer to surrounding macrophages. As a result, the target gene of miR-7e-5p, Fas ligand (FasL), was upregulated and activated the caspase signaling, which led to the apoptosis of M1 macrophages in tumor stroma. Finally, in transformed FL tissues, overexpression of FasL and activation of caspase proteins was detected in tumor stromal macrophages. Downregulation of miR-7e-5p was associated with poorer clinical outcomes.
CONCLUSION
Downregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.
背景
滤泡性淋巴瘤（FL）向高级别 FL 和弥漫性大 B 细胞淋巴瘤（DLBCL）的组织学转化是疾病进展中的一个关键不良步骤。癌基因 c-MYC 的激活和肿瘤微环境重塑解释了 FL 的进展。一组 microRNA（miRNA）在转化滤泡性淋巴瘤（tFL）中下调。
方法
在疾病不同阶段的 11 个淋巴结中系统比较差异表达的 miRNA。分析了 46 例 B 细胞淋巴瘤中的 miR-7e-5p 的表达，包括 30 例 FL 组织和 16 例 DLBCL 组织。在 FL 细胞中，通过染色质免疫沉淀（ChIP）试验揭示了癌基因 c-MYC 对其靶 miR-7e-5p 的转录调控。通过透射电子显微镜和荧光追踪分离并可视化携带差异表达 miR-7e-5p 的外泌体。在带有 miR-7e-5p-mimics 或抑制剂处理的共培养系统中，通过靶基因定量、流式细胞术和 TUNEL 方法确定 miR-7e-5p 对受体巨噬细胞的影响。进行 miR-7e-5p 靶基因、巨噬细胞比例和临床参数的相关性分析。
结果
我们确定，由 c-MYC 过表达驱动的 miR-7e-5p 的下调与 FL 患者的预后较差有关。淋巴瘤细胞中 miR-7e-5p 的表达降低导致周围巨噬细胞的外泌体转移减少。结果，miR-7e-5p 的靶基因 Fas 配体（FasL）上调并激活 caspase 信号，导致肿瘤基质中的 M1 巨噬细胞凋亡。最后，在转化的 FL 组织中，肿瘤基质巨噬细胞中 FasL 过表达和 caspase 蛋白激活被检测到。miR-7e-5p 的下调与较差的临床结局相关。
结论
下调外泌体 miR-7e-5p 诱导肿瘤基质 M1 巨噬细胞凋亡，导致 FL 的免疫监视和转化。
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