title: Zinc finger E-box binding factor 1 plays a central role in regulating Epstein-Barr virus (EBV) latent-lytic switch and acts as a therapeutic target in EBV-associated gastric cancer.
abstract: BACKGROUND
  The role of Epstein-Barr virus (EBV) infection in gastric carcinogenesis remains largely unknown. The authors studied the effects of zinc finger E-box binding factor 1 (ZEB1) on latent-lytic switch of EBV infection in gastric cancer and explored the importance of EBV in gastric carcinogenesis.
  
  
  METHODS
  Loss or gain of ZEB1 function was obtained by ZEB1 small-interfering RNA (siRNA) knock-down or forced ZEB1 re-expression. Cell growth was evaluated by cell viability and colony formation assays, and the cell cycle was assessed by flow cytometry. EBV was detected using quantitative polymerase chain reaction (PCR) and in situ hybridization analyses.
  
  
  RESULTS
  ZEB1 knock-down in a latent EBV-infected gastric cancer cell line (YCC10) increased lytic gene BamHI W leftward reading frame 1 (BZLF1) expression and decreased the expression of latent gene EB nuclear antigen 1 (EBNA1) concomitant with the inhibition of cell viability (P < .05) and S-phase DNA synthesis (P < .01). ZEB1 depletion combined with ganciclovir revealed a further reduction in cell viability (P < .001). ZEB1 knock-down induced cell apoptosis and the up-regulation of caspase 3 and poly(adenosine diphosphate-ribose) polymerase cleavage. Conversely, ectopic overexpression of ZEB1 in a lytic EBV-infected gastric cancer cell line (AGS-EBV) inhibited BZLF1 promoter (Zp) activity, BZLF1 expression, and apoptosis and promoted cell growth. EBV infection was detected in 11.3% (80 of 711) of gastric cancers. The presence of EBV was associated with age, men, and intestinal type cancer.
  
  
  CONCLUSIONS
  ZEB1 was confirmed as a key mediator of the latent-lytic switch of EBV-associated gastric cancer, a distinct subtype with different clinicopathologic features. The current results indicated that inhibition of ZEB1 may be a potential target for EBV-associated gastric cancer therapy.
authors: Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Junhong
authors: J
authors: Zhao
authors: Hongchuan
authors: H
authors: Jin
authors: Kin Fai
authors: KF
authors: Cheung
authors: Joanna H M
authors: JH
authors: Tong
authors: Sui
authors: S
authors: Zhang
authors: Minnie Y Y
authors: MY
authors: Go
authors: Linwei
authors: L
authors: Tian
authors: Wei
authors: W
authors: Kang
authors: Patrick P S
authors: PP
authors: Leung
authors: Zhirong
authors: Z
authors: Zeng
authors: Xiaoxing
authors: X
authors: Li
authors: Ka Fai
authors: KF
authors: To
authors: Joseph J Y
authors: JJ
authors: Sung
authors: Jun
authors: J
authors: Yu
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D002681:China; D004279:DNA, Viral / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000453:epidemiology / Q000378:metabolism; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000494:pharmacology; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D000970:Antineoplastic Agents; C063676:BZLF1 protein, Herpesvirus 4, Human; D004279:DNA, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C417029:EBV-encoded nuclear antigen 1