Siallyl Lewis X在小细胞外囊泡上装饰整联蛋白α3通过增强血管渗透性促进膀胱癌的转移
Sialyl Lewis X decorated integrin α3 on small extracellular vesicles promotes metastasis of bladder cancer via enhancing vascular permeability
影响因子:9.20000
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
摘要
血管的渗透性在癌细胞的扩散中起着至关重要的作用，从而促进了它们在远处的转移。已知小细胞外囊泡（Sevs）通过越过血管壁通过横穿血管壁来促进各种癌症的转移。然而，尚不清楚肿瘤血管中异常糖缀合物在SEV中的作用尚不清楚。我们的研究发现，在肌肉侵入性膀胱癌（BLCA）中，岩藻糖基转移酶VII（FUT7）及其产物SiAllyl Lewis X（Slex）升高，高水平的SLEX促进了BLCA细胞的生长和侵袭。进一步的研究表明，SLEX富含来自BLCA的SEV。通过破坏人脐静脉内皮细胞（HUVECS）的紧密连接，SLEX装饰的SEV增加了血管渗透性。使用糖蛋白质组学方法，我们将整联蛋白α3（ITGA3）鉴定为BLCA细胞中的含SLEX糖蛋白及其SEV。从机械上讲，SLEX修饰通过防止其在溶酶体中的降解来稳定ITGA3。携带SLEX修饰ITGA3的SEV可以通过HUVEC有效地内化，从而导致紧密连接蛋白的表达降低。相反，通过抑制MAPK途径，在SLEX装饰的SEV中沉默的ITGA3恢复了紧密的连接蛋白，并降低了血管渗透性。此外，HUVEC中ASN 265对ITGA3的SLEX调整促进了在Ser/Thr残基处的occludin去磷酸化，随后诱导了其Importinα1介导的核转运，从而导致紧密连接的破坏。我们的发现提出了破坏转移性微环境形成并防止恶性膀胱癌扩散的潜在策略。
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.