MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression.
MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression.
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DOI：
10.1038/ncomms14448
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发表时间：
2017-02-17
影响因子：
16.6
通讯作者：
Zhang HG
中科院分区：
文献类型：
--
作者：
Teng Y;Ren Y;Hu X;Mu J;Samykutty A;Zhuang X;Deng Z;Kumar A;Zhang L;Merchant ML;Yan J;Miller DM;Zhang HG
外泌体是细胞间通讯的新兴介质;外泌体的释放除了对受体细胞外是否对外泌体供体细胞有影响尚未在任何程度上进行研究。在这里，我们研究了不同的外泌体miRNA表达谱在原发性小鼠结肠肿瘤，结肠癌肝转移和幼稚结肠组织。在更晚期的疾病中，更高水平的肿瘤抑制miRNA被封装在外泌体中。miR-193 a与主穹窿蛋白（MVP）相互作用。MVP的敲除导致miR-193 a在外泌体供体细胞而不是外泌体中积累，从而抑制肿瘤进展。此外，miR-193 a通过靶向Caprin 1引起细胞周期G1停滞和细胞增殖抑制，Caprin 1上调Ccnd 2和c-Myc。具有更晚期疾病的人结肠癌患者显示更高水平的循环外泌体miR-193 a。总之，我们的数据表明，MVP介导的肿瘤抑制miRNA选择性分选到外泌体中促进了肿瘤进展。外泌体参与转移的发展，但其组成如何调节尚不清楚。在这里，作者提出，miR-193 a进入外泌体的主要穹窿蛋白依赖性加载可能是癌细胞摆脱抑癌miRNA的一般机制。
Exosomes are emerging mediators of intercellular communication; whether the release of exosomes has an effect on the exosome donor cells in addition to the recipient cells has not been investigated to any extent. Here, we examine different exosomal miRNA expression profiles in primary mouse colon tumour, liver metastasis of colon cancer and naive colon tissues. In more advanced disease, higher levels of tumour suppressor miRNAs are encapsulated in the exosomes. miR-193a interacts with major vault protein (MVP). Knockout of MVP leads to miR-193a accumulation in the exosomal donor cells instead of exosomes, inhibiting tumour progression. Furthermore, miR-193a causes cell cycle G1 arrest and cell proliferation repression through targeting of Caprin1, which upregulates Ccnd2 and c-Myc. Human colon cancer patients with more advanced disease show higher levels of circulating exosomal miR-193a. In summary, our data demonstrate that MVP-mediated selective sorting of tumour suppressor miRNA into exosomes promotes tumour progression. Exosomes are involved in the development of metastasis but how their composition is regulated is not well known. Here the authors propose that major vault protein-dependent loading of miR-193a into exosomes could be a general mechanism by which cancer cells get rid of oncosuppressor miRNAs.