期刊
JOURNAL OF EXTRACELLULAR VESICLES
卷 9, 期 1, 页码 -出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/20013078.2020.1722385
关键词
Exosome; tight junction; endoplasmic reticulum stress; vascular permeability; metastasis
类别
资金
- National Natural Science Foundation of China [81570251, 81528002]
- Wenzhou Municipal Science and Technology Bureau Foundation [Y20170052, Y20190163]
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 (Exo(HeLa)) on endothelial tight junctions (TJ) and the related mechanisms. After human umbilical vein endothelial cells (HUVEC) were treated with Exo(HeLa), 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 Exo(HeLa). Injection of Exo(HeLa) 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 Exo(HeLa) on ZO-1 and Claudin-5. The expression of genes involved in endoplasmic reticulum (ER) stress was significantly increased in HUVECs after treated with Exo(HeLa). 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 Exo(HeLa). 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.
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