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

Cancer Lett. 2020 May 28:478:122-132. doi: 10.1016/j.canlet.2020.03.005. Epub 2020 Mar 9.

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 (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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Epidermal Growth Factor / pharmacology
  • Epithelial-Mesenchymal Transition / drug effects
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / metabolism
  • Epstein-Barr Virus Infections / pathology*
  • Female
  • Humans
  • Mice
  • Nasopharyngeal Carcinoma / genetics
  • Nasopharyngeal Carcinoma / metabolism
  • Nasopharyngeal Carcinoma / pathology
  • Nasopharyngeal Carcinoma / virology*
  • Nasopharyngeal Neoplasms / genetics
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / pathology
  • Nasopharyngeal Neoplasms / virology*
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasm Transplantation
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism*
  • Up-Regulation*
  • Zebrafish

Substances

  • Neoplasm Proteins
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Epidermal Growth Factor