Sialyl Lewis X decorated integrin α3 on small extracellular vesicles promotes metastasis of bladder cancer via enhancing vascular permeability

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Hui Feng, Liang Liang, Wenli Deng, Jiaojiao Gao, Xiang Li, Feng Guan
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引用次数: 0

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.

Abstract Image

小细胞外囊泡上的 Sialyl Lewis X 修饰整合素 α3,通过增强血管通透性促进膀胱癌转移。
血管的通透性在癌细胞扩散过程中起着至关重要的作用,可促进癌细胞向远处转移。众所周知,细胞外小泡(sEVs)可穿过血管壁,促进各种癌症的转移。然而,肿瘤血管中sEVs上的异常糖结合物的作用仍不清楚。我们的研究发现,肌层浸润性膀胱癌(BLCA)中的岩藻糖基转移酶 VII(FUT7)及其产物 sialyl Lewis X(sLeX)水平升高,高水平的 sLeX 会促进 BLCA 细胞的生长和侵袭。进一步的研究发现,sLeX 富集在来自 BLCA 的 sEVs 中。sLeX 装饰的 sEVs 通过破坏人脐静脉内皮细胞(HUVECs)的紧密连接增加了血管的通透性。利用糖蛋白组学方法,我们发现整合素α3(ITGA3)是 BLCA 细胞及其 sEV 中含有 sLeX 的糖蛋白。携带经 sLeX 修饰的 ITGA3 的 sEV 可被 HUVECs 有效内化,从而导致紧密连接蛋白的表达下降。相反,在经 sLeX 修饰的 sEV 中沉默 ITGA3 可恢复紧密连接蛋白,并通过抑制 MAPK 通路降低血管通透性。此外,sLeX修饰HUVECs中ITGA3的Asn 265位可促进闭塞素在Ser/Thr残基上去磷酸化,继而诱导其导入素α1介导的核转位,从而导致紧密连接的破坏。我们的研究结果为破坏转移微环境的形成和防止恶性膀胱癌的扩散提供了一种潜在的策略。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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