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

Authors

  • Junhong Zhao MS,

    1. 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
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  • Hongchuan Jin PhD,

    1. 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
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  • Kin Fai Cheung PhD,

    1. 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
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  • Joanna H. M. Tong PhD,

    1. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
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  • Sui Zhang MS,

    1. Center of Liver Diseases, the First Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
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  • Minnie Y. Y. Go MD,

    1. 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
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  • Linwei Tian PhD,

    1. School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong
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  • Wei Kang PhD,

    1. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
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  • Patrick P. S. Leung MS,

    1. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
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  • Zhirong Zeng PhD,

    1. Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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  • Xiaoxing Li PhD,

    1. 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
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  • Ka Fai To MD,

    1. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
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  • Joseph J. Y. Sung MD, PhD,

    1. 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
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  • Jun Yu MD, PhD

    Corresponding author
    1. 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
    • Institute of Digestive Disease, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Room 707A, Li Ka Shing Medical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR

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    • Fax: (011) 852-21445330


  • We thank Dr. Shannon C. Kenney (Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC) for the generous gift of the AGS-EBV cell line, Dr. Jennifer Richer (Department of Pathology, University of Colorado Health Sciences Center, Aurora, Colo) for the pCI-neo-ZEB1 plasmid, and Dr. Qian Tao (Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong) for providing the YCC10 cell line.

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. Cancer 2012;. © 2011 American Cancer Society.

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