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

Journal of Experimental & Clinical Cancer Research

Jianhong Fu¹  Chao Rong²  Shan Wan²  Xin Zhao²  Shouli Wang³  Xiaoli Lou⁴  Lingchuan Guo⁵  Yongsheng Zhang⁶  Hui Niu⁶  Lu An⁶  Lei Wu⁷  Maomin Sun⁷  Xuemei Zhuansun⁷ 

[1]Department of Hematology, the First Affiliated Hospital of Soochow University, National Clinical Research Center for Hematologic Diseases, Soochow University, 215006, Suzhou, China

[2]Department of Pathology, School of Biology & Basic Medical Sciences, Soochow University, 215123, Suzhou, China

[3]Department of Pathology, School of Biology & Basic Medical Sciences, Soochow University, 215123, Suzhou, China

[4]Collaborative Innovation Center of Clinical Immunology between Soochow University and Sihong People’s Hospital, 223900, Sihong, China

[5]Department of Pathology, School of Biology & Basic Medical Sciences, Soochow University, 215123, Suzhou, China

[6]Department of Pathology, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China

[7]Department of Pathology, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China

[8]Department of Pathology, the Second Affiliated Hospital of Soochow University, 215004, Suzhou, China

[9]Laboratory Animal Research Center, Soochow University School of Medicine, 215123, Suzhou, China

关键词: Follicular lymphoma;    miR-7e;    C-MYC;    FasL;    Macrophage;    PARP;   

DOI  :  10.1186/s13046-020-01747-z

来源: Springer

【 摘 要 】

BackgroundIn 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).MethodsDifferentially 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.ResultsWe 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.ConclusionDownregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.

【 授权许可】

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