Author:
Lou Xiaoli,Fu Jianhong,Zhao Xin,Zhuansun Xuemei,Rong Chao,Sun Maomin,Niu Hui,Wu Lei,Zhang Yongsheng,An Lu,Guo Lingchuan,Wan Shan,Wang Shouli
Abstract
Abstract
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.
Funder
Collaborative Innovation Center of Clinical Immunology between Soochow University and Sihong People's Hospita
the Priority Academic Program Development of Jiangsu Higher Education Institutions
the Natural Science Foundation of the Jiangsu Higher Education Institutions of China
the Youth Program of National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Cited by
12 articles.
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