Capn4 is induced by and required for Epstein-Barr virus latent membrane protein 1 promotion of nasopharyngeal carcinoma metastasis through ERK/AP-1 signaling
Capn4 is induced by and required for Epstein-Barr virus latent membrane protein 1 promotion of nasopharyngeal carcinoma metastasis through ERK/AP-1 signaling
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Capn4 是由 Epstein-Barr 病毒潜伏膜蛋白 1 通过 ERK/AP-1 信号传导促进鼻咽癌转移所诱导和必需的
DOI：
10.1111/cas.14227
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发表时间：
2020-01-01
期刊：
影响因子：
5.7
通讯作者：
Zheng，Ming
中科院分区：
文献类型：
--
作者：
Zheng，Peichan;Chen，Xiong;Zheng，Ming
Capn 4，也称为CapnS 1，是钙蛋白酶家族的成员，在维持钙蛋白酶的活性和功能方面起着至关重要的作用。我们以前报道过Capn 4也通过核因子B活化调节MMP-2在鼻咽癌细胞迁移中起重要作用。EB巴尔病毒潜伏膜蛋白1（LMP 1）与鼻咽癌的恶性功能密切相关，但LMP 1与Capn 4在鼻咽癌中的关系尚不清楚。免疫组化结果显示，LMP 1和Capn 4在鼻咽癌原发灶和转移灶中均呈高表达，且两者呈显著正相关。我们进一步发现，LMP 1能够通过C末端激活区（CTAR）1和CTAR 2结构域以剂量依赖性方式上调Capn 4启动子，从而激活AP-1。此外，我们还发现LMP 1通过ERK/JNK磷酸化激活AP-1。这些发现表明Capn 4与LMP 1的协调促进肌动蛋白重排，并最终促进细胞迁移。这些结果表明，Capn 4与LMP 1的配位通过增加涉及ERK/JNK/AP-1信号传导的肌动蛋白重排来增强NPC迁移。在治疗上，可以利用另外的和更特异性的LMP 1和Capn 4靶向抑制剂来治疗NPC。
Capn4, also known as CapnS1, is a member of the calpain family, which plays a crucial role in maintaining the activity and function of calpain. We previously reported that Capn4 also plays an essential role in the migration of nasopharyngeal carcinoma (NPC) cells through regulation of (MMP‐2) by nuclear factor‐kappa B activation. Epstein‐Barr virus latent membrane protein 1 (LMP1) is closely related to the malignant functions of NPC; however, the relationship between LMP1 and Capn4 in NPC remain unclear. Immunohistochemical studies showed that the level of LMP1 and Capn4 expression was high in both primary and metastatic NPC tissues, with a significantly positive correlation. We further found that LMP1 was able to upregulate the Capn4 promoter in a dose‐dependent way through the C‐terminal activation region (CTAR)1 and CTAR2 domains to activate AP‐1. Moreover, we also found that LMP1 activated AP‐1 through ERK/JNK phosphorylation. These findings indicate that Capn4 coordination with LMP1 promotes actin rearrangement and, ultimately, cellular migration. These results show that Capn4 coordination with LMP1 enhances NPC migration by increasing actin rearrangement involving ERK/JNK/AP‐1 signaling. Therapeutically, additional and more specific LMP1 and Capn4 targeted inhibitors could be exploited to treat NPC.