Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma
Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma
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外泌体 miR-24-3p 通过靶向 FGF11 阻碍 T 细胞功能，并可作为鼻咽癌的潜在预后生物标志物
DOI：
10.1002/path.4781
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发表时间：
2016-11-01
影响因子：
7.3
通讯作者：
Li, Jiang
中科院分区：
文献类型：
--
作者：
Ye, Shu-Biao;Zhang, Han;Li, Jiang
最近的研究表明，细胞外microRNAs不仅是潜在的生物标志物，而且还参与细胞之间的相互作用，调节各种类型恶性肿瘤中癌细胞与其微环境之间的相互联系。在本研究中，我们从鼻咽癌(NPC)细胞系和患者血清(T-EXOS)或对照NP69细胞和健康供者血清(HD-EXOS)中分离出外切体。我们发现，与HD-EXOS相比，miR-24-3p在T-EXOS中显著丰富；血清外体miR-24-3p水平与患者的无病生存期相关(p<；0.05)。通过靶向miR-24-3p的海绵RNA敲除外体miR-24-3p(miR-24-3p-Spenge-T-EXOS)，恢复了T-EXO介导的(对照-海绵-T-EXO)对T细胞增殖和Th1和Th17分化的抑制，以及对调节性T细胞(Tregs)的诱导。机制分析表明，在T细胞增殖和分化过程中，外源miR-24-3p可增加P-ERK、P-STAT1和P-STAT3的表达，而降低P-STAT5的表达。此外，通过体内和体外评估，我们发现FGF11是miR-24-3p的直接靶点。然而，miR-24-3p-Spenge-T-EXOS和T-EXOS(Control-Spenge-T-EXOS)均抑制Lenti-shFGF11转基因T细胞的增殖和Th1、Th17分化，但诱导其Treg分化。经miR-24-3p-Spenge-T-EXO处理后，转染Lenti-ScshRNA和Lenti-shFGF11的T细胞中磷酸化ERK和STAT蛋白的表达水平不同。有趣的是，肿瘤FGF11的表达与体内CD4(+)和CD8(+)T细胞的数量呈正相关，并预测有利的患者DFS(p<；0.05)。此外，低氧还可增加细胞和胞外miR-24-3p的水平，并增强T-EXO对T细胞增殖和分化的抑制作用。综上所述，我们的研究结果表明，外体miR-24-3p可能通过抑制FGF11介导T细胞抑制而参与肿瘤的发生，并可能作为鼻咽癌潜在的预后生物标志物。版权所有(C)2016年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T-EXOs), or control NP69 cells and healthy donor sera (HD-EXOs). We found that miR-24-3p was markedly enriched in T-EXOs as compared with HD-EXOs; the serum exosomal miR-24-3p level was correlated with worse disease-free survival of patients (p < 0.05). Knockdown of exosomal miR-24-3p (miR-24-3p-sponge-T-EXOs) by a sponge RNA targeting miR-24-3p restored the T-EXO-mediated (control-sponge-T-EXO) inhibition of T-cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR-24-3p increased P-ERK, P-STAT1 and P-STAT3 expression while decreasing P-STAT5 expression during T-cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR-24-3p. However, both miR-24-3p-sponge-T-EXOs and T-EXOs (control-sponge-T-EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti-shFGF11-transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti-ScshRNA-transfected T cells and lenti-shFGF11-transfected T cells following administration of miR-24-3p-sponge-T-EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4(+) and CD8(+) T cells in vivo, and predicted favourable patient DFS (p < 0.05). Additionally, hypoxia increased cellular and exosomal miR-24-3p levels and enhanced the inhibitory effect of T-EXO on T-cell proliferation and differentiation. Collectively, our findings suggest that exosomal miR-24-3p is involved in tumour pathogenesis by mediating T-cell suppression via repression of FGF11, and may serve as a potential prognostic biomarker in NPC. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.