Nasopharyngeal carcinoma (NPC) is a unique head and neck malignancy with highly metastatic cell-biological characteristics, for which latent EBV-infection is responsible. Our earlier studies showed that EGF-stimulated Ca2+ signaling via store-operated Ca2+ entry (SOCE) was amplified in NPC cells expressing EBV-encoded LMP1, thus contributing to EBV-enhanced metastatic capacities. However, the pathway through which EBV modulates cytosolic Ca2+ signaling still remains unclear. Here, we demonstrated that EBV-infection amplified EGF-stimulated Ca2+ responses through the promotion of intracellular aggregation of STIM1, which serves as a Ca2+ sensor to activate SOCE. Blockage of EBV-remodeled Ca2+ signaling by STIM1-silencing inhibited cell migration by interrupting epithelial-mesenchymal transition (EMT) in vitro, and suppressed tumor dissemination in zebrafish and lymph node metastasis in mice. In addition, STIM1 expression was upregulated in primary NPC tissues compared with normal nasopharyngeal epithelium and stronger among the patients with advanced lymph node metastatic disease (N2-3 stage). Our findings thus indicate that EBV promotes metastatic potential by enhancing STIM1-dependent Ca2+ signaling that manipulates EMT in NPC cells. EBV-modulated Ca2+ signaling could serve as a candidate anti-metastatic target for NPC treatment.

中文翻译：

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EB病毒通过增强鼻咽癌细胞中STIM1依赖性Ca2 +信号传导来促进转移潜力。

鼻咽癌（NPC）是一种独特的头颈部恶性肿瘤，具有高度转移性的细胞生物学特征，这是潜在的EBV感染所致。我们较早的研究表明，在表达EBV编码的LMP1的NPC细胞中，EGF通过存储操作的Ca2 +进入（SOCE）刺激的Ca2 +信号被放大，从而有助于EBV增强的转移能力。但是，EBV调节细胞质Ca2 +信号传导的途径仍然不清楚。在这里，我们证明了EBV感染通过促进STIM1的细胞内聚集而增强了EGF刺激的Ca2 +应答，STIM1充当了激活SOCE的Ca2 +传感器。STIM1沉默阻止EBV重塑的Ca2 +信号传导，通过中断体外上皮-间质转化（EMT）来抑制细胞迁移，并抑制了斑马鱼中的肿瘤扩散和小鼠的淋巴结转移。此外，与正常的鼻咽上皮相比，STIM1表达在原发性鼻咽癌组织中上调，在晚期淋巴结转移性疾病（N2-3期）患者中更强。因此，我们的发现表明EBV通过增强SNP1依赖性Ca2 +信号传导（可操纵NPC细胞中的EMT）来促进转移潜力。EBV调节的Ca2 +信号传导可作为NPC治疗的候选抗转移靶标。因此，我们的发现表明EBV通过增强SNP1依赖性Ca2 +信号传导（可操纵NPC细胞中的EMT）来促进转移潜力。EBV调节的Ca2 +信号传导可作为NPC治疗的候选抗转移靶标。因此，我们的发现表明EBV通过增强SNP1依赖性Ca2 +信号传导（可操纵NPC细胞中的EMT）来促进转移潜力。EBV调节的Ca2 +信号传导可作为NPC治疗的候选抗转移靶标。