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CXCR4 induces cell autophagy and maintains EBV latent infection in EBVaGC

Authors
  • Wang, Weiwen1
  • Zhang, Yan1, 2
  • Liu, Wen1
  • Zhang, Xiangyan3
  • Xiao, Hua1
  • Zhao, Menghe1
  • Luo, Bing1
  • 1 Department of Pathogeny Biology, Basic Medicine College,Qingdao University, Qingdao 266071, China.
  • 2 Department of Clinical Laboratory, Zibo Central Hospital, ZiBo 255000, China.
  • 3 Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266071, China.
Type
Published Article
Journal
Theranostics
Publisher
Ivyspring International Publisher
Publication Date
Sep 18, 2020
Volume
10
Issue
25
Pages
11549–11561
Identifiers
DOI: 10.7150/thno.44251
PMID: 33052232
PMCID: PMC7545993
Source
PubMed Central
Keywords
License
Green

Abstract

Rationale: Epstein-Barr virus (EBV) is found in ~7% of gastric carcinoma cases worldwide, and all tumour cells harbour the clonal EBV genome. EBV can regulate pathways and protein expression to induce gastric carcinoma; however, the molecular mechanism underlying EBV-associated gastric carcinoma (EBVaGC) remains elusive. Methods: GEO microarray and molecular experiments were performed to compare CXCR4 expression between EBV-positive and EBV-negative gastric carcinoma (EBVnGC). Transfections with LMP2A plasmid or siRNA were carried out to assess the role of LMP2A in CXCR4 expression. The effects and mechanisms of CXCR4 on cell autophagy were analysed in vitro using molecular biological and cellular approaches. Additionally, we also determined the regulatory role of CXCR4 in latent EBV infection. Results: CXCR4 expression was significantly upregulated in EBVaGC tissues and cell lines. LMP2A could induce AKT phosphorylation to increase NRF1 expression, thereby binding to the CXCR4 promoter to increase its transcriptional level. Moreover, CXCR4 promoted ZEB1 expression to upregulate ATG7 synthesis, which could then activate autophagy. Moreover, CXCR4 increased the number of cells entering the G2/M phase and inhibited cell apoptosis via the autophagy pathway. Finally, CXCR4 knockdown was associated with elevated BZLF1 expression, but this effect was not influenced by autophagy. Conclusions: Our data suggested new roles for CXCR4 in autophagy and EBV replication in EBVaGC, which further promoted cell survival and persistent latent infection. These new findings can lead to further CXCR4-based anticancer therapy.

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