Epstein-Barr virus-encoded LMP2A stimulates migration of nasopharyngeal carcinoma cells via the EGFR/Ca(2+)/calpain/ITGβ4 axis.
Epstein-Barr virus-encoded LMP2A stimulates migration of nasopharyngeal carcinoma cells via the EGFR/Ca(2+)/calpain/ITGβ4 axis.
复制标题
Epstein-Barr病毒编码的LMP2A通过EGFR/Ca(2)/钙蛋白酶/ITGbeta4轴刺激鼻咽癌细胞的迁移。
DOI：
10.1242/bio.024646
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发表时间：
2017-06-15
期刊：
影响因子：
2.4
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Liang J;Zheng S;Xiao X;Wei J;Zhang Z;Ernberg I;Matskova L;Huang G;Zhou X
EB病毒编码的潜伏膜蛋白2A(LMP2A)可促进鼻咽癌(NPC)细胞的运动。以前，我们已经证明整合素β4(itgβ4)的定位受LMP2a的调节，在表达lmp2a的鼻咽癌细胞中，itgβ4主要集中在细胞突起。在本研究中，我们的目标是进一步研究参与这一过程的机制及其对细胞运动的贡献。我们发现LMP2a的表达与表皮生长因子受体的激活、细胞内钙离子浓度的升高、钙蛋白酶的激活以及对β4的加速切割有关。表皮生长因子受体的激活和钙蛋白酶的活性是导致β4从鼻咽癌细胞基底层重新分布到外周膜结构的原因，这与鼻咽癌细胞迁移能力的增强有关。此外，我们还发现，在鼻咽癌原发肿瘤中，钙蛋白酶抑制剂calastatin的表达下调。综上所述，我们的结果表明LMP2A介导的靶向EGFR/Ca~(2+)/Calain/ITGβ-4信号系统是鼻咽癌细胞运动能力增强的机制之一。我们认为，钙蛋白酶促进的β4的裂解与鼻咽癌细胞的恶性表型有关。摘要：在鼻咽癌细胞中表达LMP2a可促进表皮生长因子受体的激活和胞内钙离子浓度的升高，进而刺激钙蛋白酶依赖的β4的裂解，增强细胞的运动能力。
Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) promotes the motility of nasopharyngeal carcinoma (NPC) cells. Previously, we have shown that the localization of integrin β4 (ITGβ4) is regulated by LMP2A, with ITGβ4 concentrated at the cellular protrusions in LMP2A-expressing NPC cells. In the present study, we aim to further investigate mechanisms involved in this process and its contribution to cell motility. We show that expression of LMP2A was correlated with increased epidermal growth factor receptor (EGFR) activation, elevated levels of intracellular Ca2+, calpain activation and accelerated cleavage of ITGβ4. Activation of EGFR and calpain activity was responsible for a redistribution of ITGβ4 from the basal layer of NPC cells to peripheral membrane structures, which correlated with an increased migratory capacity of NPC cells. Furthermore, we demonstrated that the calpain inhibitor calpastatin was downregulated in NPC primary tumors. In conclusion, our results point to LMP2A-mediated targeting of the EGFR/Ca2+/calpain/ITGβ4 signaling system as a mechanism underlying the increased motility of NPC cells. We suggest that calpain-facilitated cleavage of ITGβ4 contributes to the malignant phenotype of NPC cells. Summary: LMP2A expression in nasopharyngeal carcinoma cells increases EGFR activation and cytosolic Ca2+, subsequently stimulates calpain-dependent cleavage of ITGβ4 and enhances cell motility.