Exosomes play a critical role in intercellular communication since they contain signalling molecules and genetic materials. During tumorigenesis, tumour-derived exosomes have been demonstrated to promote tumour angiogenesis and metastasis. However, how the exosomes facilitate tumour metastasis is not clear. Here we explored the effect of HeLa cell-derived exosomes (ExoHeLa) on endothelial tight junctions (TJ) and the related mechanisms. After human umbilical vein endothelial cells (HUVEC) were treated with ExoHeLa, TJ proteins zonula occludens-1 (ZO-1) and Claudin-5 in HUVEC were significantly reduced as compared with that treated with exosomes from human cervical epithelial cells, while mRNA levels of ZO-1 and Claudin-5 remained unchanged. Consequently, permeability of endothelial monolayer was increased after the treatment with ExoHeLa. Injection of ExoHeLa into mice also increased vascular permeability and tumour metastasis in vivo. Neither knocking down of Dicer nor use of inhibitors of microRNAs targeting at mRNAs of ZO-1 and Claudin-5 could block the inhibitory effect of ExoHeLa on ZO-1 and Claudin-5. The expression of genes involved in endoplasmic reticulum (ER) stress was significantly increased in HUVECs after treated with ExoHeLa. Inhibition of ER stress by knocking down protein kinase RNA-like endoplasmic reticulum kinase prevented the down-regulation of ZO-1 and Claudin-5 by ExoHeLa. Our study found that HeLa cell-derived exosomes promote metastasis by triggering ER stress in endothelial cells and break down endothelial integrity. Such effect of exosomes is microRNA-independent.

中文翻译：

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源自HeLa细胞的外泌体通过触发内皮细胞内质网应激来破坏血管完整性。

外泌体在细胞间通讯中起着至关重要的作用，因为它们含有信号分子和遗传物质。在肿瘤发生过程中，已证明肿瘤来源的外来体可促进肿瘤血管生成和转移。但是，外泌体如何促进肿瘤转移尚不清楚。在这里，我们探讨了HeLa细胞来源的外泌体（ExoHeLa）对内皮紧密连接（TJ）的影响及其相关机制。用ExoHeLa处理人脐静脉内皮细胞（HUVEC）后，HUVEC中的TJ蛋白zonula occludens-1（ZO-1）和Claudin-5与人宫颈上皮细胞外泌体相比明显减少，而mRNA水平ZO-1和Claudin-5的分子量保持不变。因此，用ExoHeLa处理后，内皮单层的通透性增加。将ExoHeLa注射到小鼠体内还增加了血管通透性和肿瘤转移。敲低Dicer或使用针对ZO-1和Claudin-5 mRNA的microRNA抑制剂都不能阻止ExoHeLa对ZO-1和Claudin-5的抑制作用。用ExoHeLa处理后，HUVEC中内质网（ER）应激相关基因的表达显着增加。通过敲低蛋白激酶RNA样内质网激酶抑制内质网应激可防止ExoHeLa对ZO-1和Claudin-5的下调。我们的研究发现，HeLa细胞来源的外泌体通过触发内皮细胞内质网应激并破坏内皮完整性来促进转移。外泌体的这种作用不依赖于微小RNA。敲低Dicer或使用针对ZO-1和Claudin-5 mRNA的microRNA抑制剂都不能阻止ExoHeLa对ZO-1和Claudin-5的抑制作用。用ExoHeLa处理后，HUVEC中内质网（ER）应激相关基因的表达显着增加。通过敲低蛋白激酶RNA样内质网激酶抑制内质网应激可防止ExoHeLa对ZO-1和Claudin-5的下调。我们的研究发现，HeLa细胞来源的外泌体通过触发内皮细胞内质网应激并破坏内皮完整性来促进转移。外泌体的这种作用不依赖于微小RNA。敲低Dicer或使用针对ZO-1和Claudin-5 mRNA的microRNA抑制剂都不能阻止ExoHeLa对ZO-1和Claudin-5的抑制作用。用ExoHeLa处理后，HUVEC中内质网（ER）应激相关基因的表达显着增加。通过敲低蛋白激酶RNA样内质网激酶抑制内质网应激可防止ExoHeLa对ZO-1和Claudin-5的下调。我们的研究发现，HeLa细胞来源的外泌体通过触发内皮细胞内质网应激并破坏内皮完整性来促进转移。外泌体的这种作用不依赖于微小RNA。用ExoHeLa处理后，HUVEC中内质网（ER）应激相关基因的表达显着增加。通过敲低蛋白激酶RNA样内质网激酶抑制内质网应激可防止ExoHeLa对ZO-1和Claudin-5的下调。我们的研究发现，HeLa细胞来源的外泌体通过触发内皮细胞内质网应激并破坏内皮完整性来促进转移。外泌体的这种作用不依赖于微小RNA。用ExoHeLa处理后，HUVEC中内质网（ER）应激相关基因的表达显着增加。通过敲低蛋白激酶RNA样内质网激酶抑制内质网应激可防止ExoHeLa对ZO-1和Claudin-5的下调。我们的研究发现，HeLa细胞来源的外泌体通过触发内皮细胞内质网应激并破坏内皮完整性来促进转移。外泌体的这种作用不依赖于微小RNA。我们的研究发现，HeLa细胞来源的外泌体通过触发内皮细胞内质网应激并破坏内皮完整性来促进转移。外泌体的这种作用不依赖于微小RNA。我们的研究发现，HeLa细胞来源的外泌体通过触发内皮细胞内质网应激并破坏内皮完整性来促进转移。外泌体的这种作用不依赖于微小RNA。