Sialyl Lewis X修饰的整合素α3在小型细胞外囊泡中促进膀胱癌转移，通过增强血管通透性实现
Sialyl Lewis X decorated integrin α3 on small extracellular vesicles promotes metastasis of bladder cancer via enhancing vascular permeability
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影响因子:9.2
分区:医学1区 Top / 外周血管病1区
发表日期:2024 Nov
作者:
Hui Feng, Liang Liang, Wenli Deng, Jiaojiao Gao, Xiang Li, Feng Guan
DOI:
10.1007/s10456-024-09947-3
摘要
血管的通透性在癌细胞扩散中起关键作用，促进其在远处的转移。小型细胞外囊泡（sEVs）已被证实在多种癌症的转移中发挥作用，能够穿越血管壁。然而，sEVs上异常糖缀的在肿瘤血管中的作用尚不明确。我们的研究发现肌层浸润性膀胱癌（BLCA）中，岩藻糖转移酶VII（FUT7）及其产物sialyl Lewis X（sLeX）水平升高，高水平的sLeX促进BLCA细胞的生长和侵袭。进一步研究显示，sLeX在BLCA来源的sEVs中富集。sLeX修饰的sEVs通过破坏人类脐静脉内皮细胞（HUVECs）的紧密连接，增加血管通透性。利用糖蛋白组学方法，鉴定出整合素α3（ITGA3）为携带sLeX的糖蛋白，在BLCA细胞及其sEVs中表达。机制上，sLeX修饰通过阻止ITGA3在溶酶体中的降解，稳定其表达。携带sLeX修饰的ITGA3的sEVs可以被HUVECs有效内吞，导致紧密连接蛋白表达下降。相反，沉默ITGA3可以恢复紧密连接蛋白，降低血管通透性，机制为抑制MAPK信号通路。此外，HUVECs中Asn 265位的sLeX修饰促进occludin在Ser/Thr残基的去磷酸化，随后引发其进口蛋白α1介导的核转运，导致紧密连接的破坏。我们的研究结果提示，通过干扰转移微环境的形成，或许能有效阻止恶性膀胱癌的扩散。
Abstract
The permeability of blood vessels plays a crucial role in the spread of cancer cells, facilitating their metastasis at distant sites. Small extracellular vesicles (sEVs) are known to contribute to the metastasis of various cancers by crossing the blood vessel wall. However, the role of abnormal glycoconjugates on sEVs in tumor blood vessels remains unclear. Our study found elevated levels of fucosyltransferase VII (FUT7) and its product sialyl Lewis X (sLeX) in muscle-invasive bladder cancer (BLCA), with high levels of sLeX promoting the growth and invasion of BLCA cells. Further investigation revealed that sLeX was enriched in sEVs derived from BLCA. sLeX-decorated sEVs increased blood vessel permeability by disrupting the tight junctions of human umbilical vein endothelial cells (HUVECs). Using the glycoproteomics approach, we identified integrin α3 (ITGA3) as a sLeX-bearing glycoprotein in BLCA cells and their sEVs. Mechanically, sLeX modification stabilized ITGA3 by preventing its degradation in lysosomes. sEVs carrying sLeX-modified ITGA3 can be effectively internalized by HUVECs, leading to a decrease in the expression of tight junction protein. Conversely, silencing ITGA3 in sLeX-decorated sEVs restored tight junction proteins and reduced blood vessel permeability by inhibiting the MAPK pathway. Moreover, sLeX-modification of ITGA3 at Asn 265 in HUVECs promoted occludin dephosphorylation at Ser/Thr residues, followed by inducing its importin α1-mediated nuclear translocation, which resulted in the disruption of tight junctions. Our findings suggest a potential strategy for disrupting the formation of a metastatic microenvironment and preventing the spread of malignant bladder cancer.