The galactoside-binding protein galectin-3 is increasingly recognized as an important player in cancer development, progression, and metastasis via its interactions with various galactoside-terminated glycans. We have shown previously that circulating galectin-3, which is increased up to 30-fold in cancer patients, promotes blood-borne metastasis in an animal cancer model. This effect is partly attributable to the interaction of galectin-3 with unknown receptor(s) on vascular endothelial cells and causes endothelial secretion of several metastasis-promoting cytokines. Here we sought to identify the galectin-3-binding molecule(s) on the endothelial cell surface responsible for the galectin-3-mediated cytokine secretion. Using two different galectin-3 affinity purification processes, we extracted four cell membrane glycoproteins, CD146/melanoma cell adhesion molecule (MCAM)/MUC18, CD31/platelet endothelial cell adhesion molecule-1 (PECAM-1), CD144/VE-cadherin, and CD106/Endoglin, from vascular endothelial cells. CD146 was the major galectin-3-binding ligand and strongly co-localized with galectin-3 on endothelial cell surfaces treated with exogenous galectin-3. Moreover, galectin-3 bound to N-linked glycans on CD146 and induced CD146 dimerization and subsequent activation of AKT signaling. siRNA-mediated suppression of CD146 expression completely abolished the galectin-3-induced secretion of IL-6 and G-CSF cytokines from the endothelial cells. Thus, CD146/MCAM is the functional galectin-3-binding ligand on endothelial cell surfaces responsible for galectin-3-induced secretion of metastasis-promoting cytokines. We conclude that CD146/MCAM interactions with circulating galectin-3 may have an important influence on cancer progression and metastasis.

译文

半乳糖苷结合蛋白galectin-3通过与各种半乳糖苷末端聚糖的相互作用,越来越被认为是癌症发展,进展和转移的重要参与者。我们先前已经证明,在动物癌症模型中,循环galectin-3在癌症患者中增加了30倍,可促进血源性转移。这种作用部分归因于galectin-3与血管内皮细胞上未知受体的相互作用,并引起内皮分泌几种促进转移的细胞因子。在这里,我们试图鉴定内皮细胞表面负责galectin-3-mediated细胞因子分泌的galectin-3-binding分子。使用两种不同的galectin-3亲和纯化过程,我们从血管内皮细胞中提取了四种细胞膜糖蛋白,CD146/黑色素瘤细胞粘附分子 (MCAM)/MUC18,CD31/血小板内皮细胞粘附分子-1 (PECAM-1),CD144/VE-钙粘蛋白和CD106/Endoglin。CD146是主要的galectin-3-binding配体,与galectin-3强烈共定位在用外源galectin-3处理的内皮细胞表面上。此外,galectin-3与CD146上的N-连接聚糖结合并诱导CD146二聚化和随后AKT信号传导的激活。siRNA介导的CD146表达抑制完全消除了内皮细胞galectin-3-induced分泌IL-6和g-csf细胞因子。因此,CD146/MCAM是内皮细胞表面的功能性galectin-3-binding配体,负责galectin-3-induced分泌促进转移的细胞因子。我们得出结论,CD146/MCAM与循环galectin-3的相互作用可能对癌症的进展和转移有重要影响。

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