Back to Journals » Cancer Management and Research » Volume 10

Blockage of store-operated Ca2+ entry antagonizes Epstein–Barr virus-promoted angiogenesis by inhibiting Ca2+ signaling-regulated VEGF production in nasopharyngeal carcinoma

Authors Ye J, Huang J, He Q, Zhao W, Zhou X, Zhang Z, Li Y, Wei J, Zhang J

Received 10 December 2017

Accepted for publication 26 February 2018

Published 10 May 2018 Volume 2018:10 Pages 1115—1124


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Kenan Onel

Jiaxiang Ye,1 Junqi Huang,2 Qian He,3 Weilin Zhao,4 Xiaoying Zhou,5 Zhe Zhang,4 Yongqiang Li,1 Jiazhang Wei,6 Jinyan Zhang1

1Department of Medical Oncology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning 530021, People’s Republic of China; 2Department of Pathology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning 530021, People’s Republic of China; 3Institute for the Advancement of Higher Education, Hokkaido University, Sapporo, Japan; 4Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, People’s Republic of China; 5Life Science Institute, Guangxi Medical University, Nanning 530021, People’s Republic of China; 6Department of Otolaryngology and Head and Neck Oncology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, People’s Republic of China

Background: Epstein–Barr virus (EBV) actively contributes to the pathological process of nasopharyngeal carcinoma (NPC) by enabling NPC cells to acquire various capacities required for their malignant biological actions. Our earlier works demonstrated that EBV-encoded latent membrane protein 1 (LMP1) enhanced vascular endothelial growth factor (VEGF)-mediated angiogenesis by boosting store-operated Ca2+ entry (SOCE) upon extracellular epidermal growth factor (EGF) stimulation. However, the antagonistic effects of SOCE blockage on EBV-promoted angiogenesis must be appropriately evaluated in vivo, and the global effect of EBV infection on the EGF-elicited cytosolic Ca2+ signaling, which regulates VEGF-mediated angiogenesis remains to be further clarified.
Materials and methods: Two EBV-infected NPC cell lines, CNE2-EBV and HK1-EBV, along with their parental cell lines were employed in the present study. Dynamic cytosolic Ca2+ changes were measured in individual fluorescent Ca2+ indicator-loaded cells. Amounts of VEGF production were determined by enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs)-formed tube networks were quantitatively evaluated as an in vitro angiogenesis assay. A mouse model concurrently bearing EBV-positive/negative xenografts was utilized to evaluate the tumor growth and angiogenesis in vivo.
Results: EBV infection reliably promoted transplanted tumor growth while enhancing angiogenesis. Introduction of EBV into EBV-negative NPC cells increased the EGF-stimulated VEGF production while amplifying the EGF-evoked Ca2+ responses. Inhibition of the EBV-boosted Ca2+ signaling using 2-aminoethyl diphenylborinate (2-APB), a specific SOCE inhibitor, effectively antagonized the EBV-promoted VEGF production and endothelial tube formation in vitro. Pharmacological blockage of SOCE exhibited anti-angiogenic effect in the EBV-positive xenografts.
Conclusion: SOCE can serve as a candidate pharmacological target for treating NPC, as blockage of the Ca2+ signaling via SOCE is a feasible strategy to suppress the EBV-driven malignant profiles in NPC cells.

Keywords: nasopharyngeal carcinoma, store-operated Ca2+ entry, angiogenesis, Epstein–Barr virus, vascular endothelial growth factor

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]