Melanoma‐released exosomes directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo
Melanoma‐released exosomes directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo
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DOI：
10.1016/j.yexcr.2018.08.030
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发表时间：
2018-08
影响因子：
3.7
通讯作者：
Ji Zhou;Yi Yang;Wenwen Wang;Y. Zhang;Zhengrong Chen;Chuangli Hao;Jinping Zhang
中科院分区：
文献类型：
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作者：
Ji Zhou;Yi Yang;Wenwen Wang;Y. Zhang;Zhengrong Chen;Chuangli Hao;Jinping Zhang
肿瘤源性外泌体（TEX）在肿瘤细胞逃避免疫监视中起重要作用。然而，该机制的细节尚未完全了解。在这项研究中，在体外和体内用B16衍生的外泌体治疗期间，CD 4 +T细胞的凋亡增加，导致小鼠黑色素瘤细胞的生长加速。虽然通过破坏Rab 27 a的表达来阻断外泌体的释放，但肿瘤生长明显受到抑制，并且肿瘤环境中T细胞的百分比增加。Western blot结果显示，TEX可激活caspase-3、caspase-7和caspase-9，但对caspase-8无明显影响，并下调抗凋亡蛋白BCL-2、MCL-1和BCL-xL的表达，提示TEX可激活CD 4 +T细胞的线粒体凋亡途径。这些减少可能与从TEX向T细胞释放microRNA（如miR-690）有关。我们目前的研究首次揭示了黑色素瘤释放的外泌体可能通过其microRNA货物直接激活CD 4 +T细胞的线粒体凋亡途径。
Tumor-derived exosomes (TEX) play an important role in the escape of tumor cells from immune surveillance. However, the details of the mechanism are not fully understood. In this study, the apoptosis of CD4+T cells increased during treatment with B16-derived exosomes in vitro and in vivo, resulting in accelerated growth of melanoma cells in mice. While the release of exosomes was blocked by disrupting the expression of Rab27a, tumor growth was clearly inhibited, and the percentage of T cells in the tumor environment increased. At the same time, Western blot showed that TEX could increase the activation of caspase-3, caspase-7 and caspase-9 but not caspase-8, down-regulating the anti-apoptotic proteins, including BCL-2, MCL-1 and BCL-xL in CD4+T cells, and indicating that the TEX activates the mitochondrial apoptotic pathway of CD4+T cells. These reductions were probably associated with the release of microRNAs, such as miR-690, from TEX to T cells. Our present study reveals for the first time that melanoma-released exosomes may directly activate the mitochondrial apoptotic pathway of CD4+T cells through their microRNA cargo.