EB virus promotes metastatic potential by boosting STIM1-dependent Ca2+ signaling in nasopharyngeal carcinoma cells

Abstract

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 (N_2-3 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.

Keywords: Epithelial-mesenchymal transition; Epstein–barr virus; Metastasis; Migration; STIM1.