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GD3/GD2 阳性胶质瘤细胞来源的外泌体在调节表型和细胞内信号传导中的作用机制：整合素的作用

Action Mechanisms of Exosomes Derived from GD3/GD2-Positive Glioma Cells in the Regulation of Phenotypes and Intracellular Signaling: Roles of Integrins.

作者信息

Hasnat Mohammad Abul, Ohmi Yuhsuke, Yesmin Farhana, Kaneko Kei, Kambe Mariko, Kitaura Yoko, Ito Takako, Imao Yuka, Kano Keiko, Mishiro-Sato Emi, Koyanagi Hiroka, Kawamoto Yoshiyuki, Bhuiyan Robiul Hasan, Ohkawa Yuki, Tajima Orie, Furukawa Koichi, Furukawa Keiko

机构信息

Department of Biomedical Sciences, Chubu University, Matsumoto 1200, Kasugai 487-8501, Aichi, Japan.

Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh.

出版信息

Int J Mol Sci. 2024 Nov 27;25(23):12752. doi: 10.3390/ijms252312752.

DOI:10.3390/ijms252312752
PMID:39684463
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11641595/
Abstract

Extracellular vesicles (EVs) play important roles in intercellular communication in various biological events. In particular, EVs released from cancer cells have attracted special attention. Although it has been reported that cancer-associated glycosphingolipids play important roles in the enhancement of malignant properties of cancer cells, the presence, behavior, and roles of glycosphingolipids in EVs have not been elucidated. Recently, we reported crucial roles of EVs expressing gangliosides, GD2, and/or GD3 in the enhancement of cancer properties in malignant melanomas and gliomas. However, how EVs containing cancer-associated glycosphingolipids play their roles has not been reported to date. Here, we studied spatio-temporal mechanisms for GD3/GD2-containing EVs released from gliomas in the actions toward target cells. Proteome analyses of EVs with/without GD3/GD2 revealed an equally high concentration of integrin isoforms in both GD3/GD2+ and GD3/GD2- EVs. PKH26-labeled EVs attached, invaded, and distributed to/in the target cells within 1 h. GD3/GD2 formed molecular complexes with integrins on EVs as elucidated by immunoprecipitation/immunoblotting and immunocytostaining. The addition of antibodies reactive with GD3, GD2, or integrins resulted in the suppression of the enhancing effects of EVs in the cell adhesion assay. The addition of GD3/GD2 + EVs to GD3/GD2- cells clearly increased the phosphorylation levels of the PDGF receptor, FAK, and Erk1/2 in immunoblotting, suggesting GD3/GD2+ EVs activate the signaling pathway in the target cells within 15 min after addition. Anti-ganglioside antibodies clearly blocked signaling with EVs. In conclusion, EVs released from GD3/GD2-expressing glioma cells enhance cancer phenotypes and malignant signals via the cluster formation of integrins and GD3/GD2 on EVs, leading to the regulation of the cancer microenvironment.

摘要

细胞外囊泡（EVs）在各种生物事件的细胞间通讯中发挥着重要作用。特别是，癌细胞释放的EVs引起了特别关注。尽管有报道称癌症相关糖鞘脂在增强癌细胞恶性特性方面发挥重要作用，但糖鞘脂在EVs中的存在、行为和作用尚未阐明。最近，我们报道了表达神经节苷脂、GD2和/或GD3的EVs在恶性黑色素瘤和神经胶质瘤中增强癌症特性方面的关键作用。然而，迄今为止，含有癌症相关糖鞘脂的EVs如何发挥其作用尚未见报道。在此，我们研究了神经胶质瘤释放的含GD3/GD2的EVs作用于靶细胞的时空机制。对含有/不含有GD3/GD2的EVs进行蛋白质组分析发现，GD3/GD2+和GD3/GD2- EVs中整合素异构体的浓度同样高。PKH26标记的EVs在1小时内附着、侵入并分布到靶细胞内/中。通过免疫沉淀/免疫印迹和免疫细胞化学分析表明，GD3/GD2与EVs上的整合素形成分子复合物。在细胞黏附试验中，添加与GD3、GD2或整合素反应的抗体导致EVs增强作用的抑制。在免疫印迹中，向GD3/GD2-细胞中添加GD3/GD2 + EVs明显增加了血小板衍生生长因子受体（PDGF受体）、粘着斑激酶（FAK）和细胞外信号调节激酶1/2（Erk1/2）的磷酸化水平，表明GD3/GD2+ EVs在添加后15分钟内激活了靶细胞中的信号通路。抗神经节苷脂抗体明显阻断了与EVs的信号传导。总之，从表达GD3/GD2的神经胶质瘤细胞释放的EVs通过EVs上整合素和GD3/GD2的簇集形成增强癌症表型和恶性信号，从而导致癌症微环境的调节。

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Isocitrate dehydrogenase 1 upregulation in urinary extracellular vesicles from proximal tubules of type 2 diabetic rats.2 型糖尿病大鼠近端肾小管尿细胞外囊泡中异柠檬酸脱氢酶 1 的上调。
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Extracellular vesicles from non-neuroendocrine SCLC cells promote adhesion and survival of neuroendocrine SCLC cells.
非神经内分泌小细胞肺癌细胞的细胞外囊泡促进神经内分泌小细胞肺癌细胞的黏附和存活。
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The role of lipid rafts in vesicle formation.脂质筏在囊泡形成中的作用。
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