p38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly
p38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly
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DOI：
10.1152/ajpcell.00242.2009
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发表时间：
2010-05-01
影响因子：
5.5
通讯作者：
Dong, Cheng
中科院分区：
文献类型：
--
作者：
Khanna, Payal;Yunkunis, Tara;Dong, Cheng
Khanna P、Yunkunis T、Muddana HS、Peng HH、August A、Dong C。 p38 MAP 激酶对于黑色素瘤介导的 VE-钙粘蛋白解体调节是必需的。 Am J Physiol Cell Physiol 298：C1140-C1150，2010。首次发表于 2010 年 2 月 24 日； doi:10.1152/ajpcell.00242.2009.-血管内皮 (VE)-钙粘蛋白定位于内皮边界和粘附连接，受丝裂原激活蛋白 (MAP) 激酶、GTP 酶和细胞内钙的变化调节。我们之前表明，黑色素瘤细胞通过与共培养的人脐静脉内皮细胞接触来诱导 VE-钙粘蛋白解体。然而，黑色素瘤细胞向内皮细胞发出信号以诱导 VE-钙粘蛋白连接解体的确切机制尚不清楚。在这项研究中，在荧光显微镜下进一步检查了 VE-钙粘蛋白连接的分解。我们发现，黑色素瘤诱导的内皮细胞中 VE-钙粘蛋白连接解体和 p38 MAP 激酶上调受到黑色素瘤可溶性因子（特别是白细胞介素 (IL)-8、IL-6 和 IL-1 beta）和血管细胞粘附分子 1 的调节。中和黑色素瘤分泌的可溶性因子可减少内皮间隙的形成。用 MAP 激酶激酶 6（p38 MAP 激酶的直接激活剂）转染的内皮细胞，增加了 VE-钙粘蛋白介导的间隙形成，促进黑色素瘤跨内皮迁移。相比之下，在博伊登室实验中，用针对 p38 MAP 激酶表达的小干扰 RNA 转染的内皮细胞在很大程度上阻止了黑色素瘤跨内皮迁移。这些发现表明 p38 MAP 激酶蛋白调节 VE-钙粘蛋白连接解体，促进黑色素瘤跨内皮细胞迁移。
Khanna P, Yunkunis T, Muddana HS, Peng HH, August A, Dong C. p38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly. Am J Physiol Cell Physiol 298: C1140-C1150, 2010. First published February 24, 2010; doi:10.1152/ajpcell.00242.2009.-Vascular endothelial (VE)-cadherin is localized to the endothelial borders and the adherens junctions, which are regulated by changes in mitogen-activated protein (MAP) kinases, GTPases, and intracellular calcium. We previously showed that melanoma cells induce VE-cadherin disassembly through contact with human umbilical vein endothelial cells in coculture. However, the exact mechanism by which melanoma cells signal endothelial cells to induce VE-cadherin junction disassembly is not well understood. In this study, VE-cadherin junction disassembly was further examined under fluorescence microscopy. We found that melanoma-induced VE-cadherin junction disassembly and upregulation of p38 MAP kinase in endothelial cells is regulated by both soluble factors from melanomas, particularly interleukin (IL)-8, IL-6, and IL-1 beta, and through vascular cell adhesion molecule-1. Neutralizing melanoma-secreted soluble factors reduced endothelial gap formation. Endothelial cells transfected with MAP kinase kinase 6, a direct activator of p38 MAP kinase, increased VE-cadherin-mediated gap formation, facilitating melanoma transendothelial migration. In contrast, endothelial cells transfected with small-interfering RNA against p38 MAP kinase expression largely prevented melanoma transendothelial migration in Boyden chamber experiments. These findings indicate that p38 MAP kinase proteins regulate VE-cadherin junction disassembly, facilitating melanoma migration across endothelial cells.