EBV latent membrane protein 1 effects on plakoglobin, cell growth, and migration.
EBV latent membrane protein 1 effects on plakoglobin, cell growth, and migration.
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DOI：
10.1158/0008-5472.can-08-1178
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Raab-Traub N
中科院分区：
文献类型：
--
作者：
Shair KH;Schnegg CI;Raab-Traub N
潜伏膜蛋白-1（LMP 1）是EB病毒（EBV）的主要癌蛋白，可能是导致包括鼻咽癌（NPC）在内的EBV相关癌症中许多细胞生长特性改变的原因。在这项研究中，LMP 1对细胞生长和迁移的影响进行了研究的背景下，EBV阳性的C666-1鼻咽癌细胞系。在软琼脂转化和transwell转移试验中，LMP 1通过激活磷脂酰肌醇3-激酶（PI 3 K）/Akt和NFκB信号增强细胞生长和迁移。PI 3 K、Akt和NFκB信号传导的抑制剂显著降低了这些增强的性质。IκBα超阻遏物也阻断了这些作用。然而，Akt单独的组成性激活并不改变细胞生长，这表明LMP 1需要PI 3 K/Akt和NFκB激活。这些增强的作用需要全长LMP 1，其包含PI 3 K/Akt活化C末端活化区（CTAR）1和非冗余NFκB活化区CTAR 1和2。LMP 2A是一种潜伏蛋白，也经常在NPC中表达，类似地激活PI 3 K/Akt通路，然而其在C666-1细胞中的过表达不影响细胞生长或迁移。LMP 1还降低了连接蛋白斑珠蛋白的表达，斑珠蛋白被证明是LMP 1诱导的增强的迁移的部分原因。这项研究表明，在上皮细胞中，LMP 1的转化特性需要激活PI 3 K/Akt和NFκB，并证明LMP 1的斑珠蛋白表达的缺失是增强迁移的重要因素。
Latent membrane protein-1 (LMP1), the major oncoprotein of Epstein-Barr virus (EBV), is likely responsible for many of the altered cellular growth properties in EBV-associated cancers including nasopharyngeal carcinoma (NPC). In this study, the effects of LMP1 on cell growth and migration were studied in the context of the EBV-positive C666-1 NPC cell line. In the soft agar transformation and transwell metastasis assays, LMP1 enhanced cell growth and migration through activation of phosphatidylinositol 3-kinase (PI3K)/Akt and NFκB signaling. Inhibitors of PI3K, Akt and NFκB signaling dramatically reduced these enhanced properties. An IκBα super-repressor also blocked these effects. However, constitutive activation of Akt alone did not alter cell growth, suggesting that both PI3K/Akt and NFκB activation are required by LMP1. These enhanced effects required the full-length LMP1 encompassing both the PI3K/Akt activating C-terminal activation region (CTAR) 1 and the non-redundant NFκB activating regions CTARs 1 and 2. LMP2A, a latent protein that is also frequently expressed in NPC, similarly activates the PI3K/Akt pathway, however its over-expression in C666-1 cells did not affect cell growth or migration. LMP1 also decreased expression of the junctional protein plakoglobin which was shown to be partially responsible for enhanced migration induced by LMP1. This study reveals that in epithelial cells the transforming properties of LMP1 require activation of both PI3K/Akt and NFκB and demonstrates that the loss of plakoglobin expression by LMP1 is a significant factor in the enhanced migration.