Endothelial LGALS9 splice variant expression in endothelial cell biology and angiogenesis
Endothelial LGALS9 splice variant expression in endothelial cell biology and angiogenesis
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DOI：
10.1016/j.bbadis.2013.12.003
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发表时间：
2014-02-01
影响因子：
6.2
通讯作者：
Thijssen, Victor L.
中科院分区：
文献类型：
--
作者：
Heusschen, Roy;Schulkens, Iris A.;Thijssen, Victor L.
半乳糖凝集素是在肿瘤进展中具有多功能的碳水化合物结合蛋白。半乳糖凝集素-9由LGALS 9编码，与转移和免疫抑制相关。我们先前报道了在内皮细胞活化过程中LGALS 9表达的调节。在这里，我们显示了不同肿瘤的内皮细胞中半乳糖凝集素-9蛋白水平的增加，包括肺癌、肝癌、乳腺癌和肾癌。发现内皮细胞表达五种LGALS 9剪接变体，其中两种以前没有报道过。剪接被发现局限于外显子5，6和10。用半乳糖凝集素-9 Δ 5（一种特异性LGALS 9剪接变体）转染人微血管内皮细胞（HMEC），诱导增殖的小但显著增加，而迁移不受任何LGALS 9剪接变体的影响。应用重组半乳糖凝集素-9 δ 5蛋白在体外剂量依赖性地降低HMEC以及人脐静脉内皮细胞的增殖和迁移。人脐静脉内皮细胞（HUVEC）向半乳糖凝集素-9 δ 5梯度的生长和迁移增强。有趣的是，发现半乳糖凝集素-9 δ 5在体内诱导对血管生成的小抑制作用。总的来说，这些数据表明，内皮细胞调节血管生成过程中LGALS 9的表达和剪接。显性剪接变体，即半乳糖凝集素-9 δ 5在内皮细胞生物学中的功能取决于其呈递给细胞的浓度和环境背景。(C)2013 Elsevier B. V.保留所有权利。
Galectins are carbohydrate binding proteins with versatile functions in tumor progression. Galectin-9, encoded by LGALS9, has been associated with metastasis and immunosuppression. We previously reported on regulation of LGALS9 expression during endothelial cell activation. Here, we show increased galectin-9 protein levels in the endothelium of different tumors, including carcinomas of the lung, liver, breast and kidney. Endothelial cells were found to express five LGALS9 splice variants, two of which have not been reported before. Splicing was found to be confined to exons 5,6 and 10. Transfection of human microvascular endothelial cells (HMEC) with galectin-9 Delta 5, a specific LGALS9 splice variant, induced a small but significant increase of proliferation, while migration was not affected by any LGALS9 splice variant. Application of recombinant galectin-9 Delta 5 protein dose-dependently reduced proliferation and migration of HMEC as well as human umbilical vein endothelial cells in vitro. Enhanced sprouting and migration of human umbilical vein endothelial cell (HUVEC) towards a galectin-9 Delta 5 gradient were observed. Interestingly, galectin-9 Delta 5 was found to induce a small inhibitory effect on angiogenesis in vivo. Collectively, these data show that endothelial cells regulate the expression and splicing of LGALS9 during angiogenesis. The function of the dominant splice variant, i.e. galectin-9 Delta 5, in endothelial cell biology depends on the concentration and environmental context in which it is presented to the cells. (C) 2013 Elsevier B.V. All rights reserved.