Blockage of LMP1-modulated store-operated Ca2+ entry reduces metastatic potential in nasopharyngeal carcinoma cell
Blockage of LMP1-modulated store-operated Ca2+ entry reduces metastatic potential in nasopharyngeal carcinoma cell
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DOI：
10.1016/j.canlet.2015.02.032
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发表时间：
2015-05-01
期刊：
影响因子：
9.7
通讯作者：
Watanabe, Hiroshi
中科院分区：
文献类型：
--
作者：
Wei, Jiazhang;Zhang, Jinyan;Watanabe, Hiroshi
EB病毒(EBV)编码的潜伏膜蛋白(LMPs)加速了EBV相关癌症的进展。在全套LMPs中，潜伏膜蛋白1(LMP1)被鉴定为唯一能增强钙库操纵性钙内流(SOCE)的蛋白。此前，我们报道了抑制SOCE对EBV阴性鼻咽癌(NPC)细胞的迁移和血管外渗的抑制作用。在这项后续研究中，我们旨在扩大我们对LMP1调节SOCE的理解，并测试阻断LMP1调节的SOCE影响LMP1促进的转移潜能的可能性。在体外，我们发现抑制LMP1促进的SOCE可以钝化LMP1促进的细胞迁移、血管生成和通透性。阻断SOCE可抑制体内循环细胞的血管侵袭和远处转移定植。值得注意的是，利用VEGFR2-EGFP-Tag斑马鱼，我们发现在小口径血管中滞留的LMP1表达细胞动员周围的内皮细胞，以促进血管系统的入侵。因此，LMP1增强的SOCE通过操纵致癌的钙信号，巩固了鼻咽癌细胞与附近非肿瘤细胞的合作，从而促进了鼻咽癌细胞的转移潜能。我们的研究强调了使用传统哺乳动物和转基因斑马鱼来开发一种针对多步骤侵袭-转移级联反应的新的治疗策略的优势。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
Epstein-Barr virus (EBV)-encoded latent membrane proteins (LMPs) expedite progression of EBV-relevant cancers. Of the full set of LMPs, latent membrane protein 1 (LMP1) was identified to uniquely augment store-operated Ca2+ entry (SOCE). Previously, we reported that the suppression of SOCE exhibited inhibitory effects on cell migration and the extravasation from vasculature in EBV-negative nasopharyngeal carcinoma (NPC) cells. In this follow-up study, we aimed to expand our understanding of the modulation of SOCE by LMP1 and test the possibility that blockage of LMP1-modulated SOCE affects the LMP1-promoted metastatic potential. Here we showed that suppressions of the LMP1-boosted SOCE blunted the LMP1-promoted cell migration, VEGF-mediated angiogenesis and permeabilization in vitro. Blockage of SOCE inhibited vasculature-invasion of circulating cells and distant metastatic colonization in vivo. Notably, utilizing VEGFR2-EGFP-tag zebrafish we revealed that the LMP1-expressing cells arrested in a small-caliber vessel mobilized surrounding endothelial cells to facilitate vasculature-invasion. Thus, the LMP1-boosted SOCE promotes metastatic potential of NPC cells by solidifying their collaborations with the nearby non-cancer cells through the manipulation of oncogenic Ca2+ signaling. Our study highlights the advantage of using both conventional mammal and transgenic zebrafish for developing a novel therapeutic strategy targeting the multiple steps of invasion-metastasis cascade. (C) 2015 Elsevier Ireland Ltd. All rights reserved.