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Epstein–Barr virus immediate-early protein Zta mediates the proliferation and migration of HER2-overexpressing cancer cells

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Abstract

Epstein–Barr virus immediate-early protein Zta plays an active role in altering cellular gene expression, which may be fundamentally linked to the viral life cycle, cell cycle, cell growth, and differentiation. HER2 is associated with a wide variety of human cancers, and its knockdown significantly reverses the malignant features of HER2-positive cancers. The aim of this study was to investigate the potential role of Zta in regulating HER2 expression and phenotype changes of MDA-MB-453 cells. Our results indicate that ectopic expression of Zta resulted in downregulation of the HER2 protein in cancer cells (MDA-MB-453, SKBR-3, BT474, and SKOV-3). The Zta protein significantly decreased HER2 mRNA and protein expression in MDA-MB-453 cells in a dose-dependent manner. Mechanistically, Zta recognized and targeted the promoter of HER2 gene, reducing the transcriptional activity of the HER2 gene. Zta induced G0/G1 arrest of MDA-MB-453 cells, inhibiting their proliferation and migration activity. These data suggest that Zta may act as a transforming suppressor of the HER2 gene.

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Data availability

The datasets generated and/or analysed in the current study are available from the corresponding author on reasonable request.

References

  1. Shannon-Lowe C, Rickinson AB, Bell AI (2017) Epstein–Barr virus-associated lymphomas. Philos Trans R Soc Lond B Biol Sci. https://doi.org/10.1098/rstb.2016.0271

    Article  PubMed  PubMed Central  Google Scholar 

  2. Yanagi A, Nishikawa J, Shimokuri K, Shuto T, Takagi T, Takagi F et al (2019) Clinicopathologic characteristics of Epstein-Barr virus-associated gastric cancer over the past decade in Japan. Microorganisms. https://doi.org/10.3390/microorganisms7090305

    Article  PubMed  PubMed Central  Google Scholar 

  3. Khan G, Fitzmaurice C, Naghavi M, Ahmed LA (2020) Global and regional incidence, mortality and disability-adjusted life-years for Epstein-Barr virus-attributable malignancies, 1990–2017. BMJ Open 10(8):e037505. https://doi.org/10.1136/bmjopen-2020-037505

    Article  PubMed  PubMed Central  Google Scholar 

  4. Al Hamad M, Matalka I, Al Zoubi MS, Armogida I, Khasawneh R, Al-Husaini M et al (2020) Human mammary tumor virus, human papilloma virus, and Epstein-Barr Virus infection are associated with sporadic breast cancer metastasis. Breast Cancer (Auckl). https://doi.org/10.1177/1178223420976388

    Article  PubMed  Google Scholar 

  5. Gopalakrishnan Mahalingam KK, Sankar LS, Masthan KMK, Mahalakshmi K, Naveen Kumar V (2021) Epstein–Barr viral load in exfoliated cells of oral squamous cell carcinoma and oral potentially malignant disorders—a cross-sectional study. J Clin Virol Plus 1(4):100051. https://doi.org/10.1016/j.jcvp.2021.100051

    Article  Google Scholar 

  6. Godfrey A, Osborn K, Sinclair AJ (2021) Interaction sites of the Epstein-Barr virus Zta transcription factor with the host genome in epithelial cells. Access Microbiol 3(11):000282. https://doi.org/10.1099/acmi.0.000282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhou Y, Heesom K, Osborn K, AlMohammed R, Sweet SM, Sinclair AJ (2020) Identifying the cellular interactome of Epstein–Barr virus lytic regulator zta reveals cellular targets contributing to viral replication. J Virol. https://doi.org/10.1128/jvi.00927-19

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ramasubramanyan S, Osborn K, Al-Mohammad R, Naranjo Perez-Fernandez IB, Zuo J, Balan N et al (2015) Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression. Nucleic Acids Res 43(7):3563–3577. https://doi.org/10.1093/nar/gkv212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cayrol C, Flemington E (1996) The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin‐dependent kinase inhibitors. EMBO J 15(11):2748–2759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tsai S-C, Lin S-J, Chen P-W, Luo W-Y, Yeh T-H, Wang H-W, Chen C-J, Tsai C-H (2009) EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines. Blood J Am Soc Hematol 114(1):109–118

    CAS  Google Scholar 

  11. Kang M-S, Kieff E (2015) Epstein–Barr virus latent genes. Exp Mol Med 47(1):e131–e. https://doi.org/10.1038/emm.2014.84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Young LS, Murray PG (2003) Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene 22(33):5108–5121. https://doi.org/10.1038/sj.onc.1206556

    Article  CAS  PubMed  Google Scholar 

  13. Marquitz AR, Mathur A, Shair KH, Raab-Traub N (2012) Infection of Epstein-Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression. Proc Natl Acad Sci U S A 109(24):9593–9598. https://doi.org/10.1073/pnas.1202910109

    Article  PubMed  PubMed Central  Google Scholar 

  14. Luo Y, Liu Y, Wang C, Gan R (2021) Signaling pathways of EBV-induced oncogenesis. Cancer Cell Int 21(1):93. https://doi.org/10.1186/s12935-021-01793-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cayrol C, Flemington EK (1996) The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors. Embo J 15(11):2748–2759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rodriguez A, Jung EJ, Yin Q, Cayrol C, Flemington EK (2001) Role of c-myc regulation in Zta-mediated induction of the cyclin-dependent kinase inhibitors p21 and p27 and cell growth arrest. Virology 284(2):159–169. https://doi.org/10.1006/viro.2001.0923

    Article  CAS  PubMed  Google Scholar 

  17. Mauser A, Holley-Guthrie E, Zanation A, Yarborough W, Kaufmann W, Klingelhutz A, Seaman WT, Kenney S (2002) The Epstein-Barr virus immediate-early protein BZLF1 induces expression of E2F-1 and other proteins involved in cell cycle progression in primary keratinocytes and gastric carcinoma cells. J Virol 76(24):12543–12552. https://doi.org/10.1128/jvi.76.24.12543-12552.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sundaresan S, Penuel E, Sliwkowski MX (1999) The biology of human epidermal growth factor receptor 2. Curr Oncol Rep 1(1):16–22. https://doi.org/10.1007/s11912-999-0005-7

    Article  CAS  PubMed  Google Scholar 

  19. Lee J, Dull TJ, Lax I, Schlessinger J, Ullrich A (1989) HER2 cytoplasmic domain generates normal mitogenic and transforming signals in a chimeric receptor. Embo J 8(1):167–173. https://doi.org/10.1002/j.1460-2075.1989.tb03361.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. De Potter IY, Poumay Y, Squillace KA, Pittelkow MR (2001) Human EGF receptor (HER) family and heregulin members are differentially expressed in epidermal keratinocytes and modulate differentiation. Exp Cell Res 271(2):315–328. https://doi.org/10.1006/excr.2001.5390

    Article  CAS  PubMed  Google Scholar 

  21. Villa-Moruzzi E (2011) Tyrosine phosphatases in the HER2-directed motility of ovarian cancer cells: Involvement of PTPN12, ERK5 and FAK. Anal Cell Pathol (Amst) 34(3):101–112. https://doi.org/10.3233/acp-2011-0008

    Article  CAS  PubMed  Google Scholar 

  22. Carpenter RL, Han W, Paw I, Lo HW (2013) HER2 phosphorylates and destabilizes pro-apoptotic PUMA, leading to antagonized apoptosis in cancer cells. PLoS ONE 8(11):e78836. https://doi.org/10.1371/journal.pone.0078836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kunte S, Abraham J, Montero AJ (2020) Novel HER2-targeted therapies for HER2-positive metastatic breast cancer. Cancer 126(19):4278–4288. https://doi.org/10.1002/cncr.33102

    Article  CAS  PubMed  Google Scholar 

  24. Faltus T, Yuan J, Zimmer B, Krämer A, Loibl S, Kaufmann M, Strebhardt K (2004) Silencing of the HER2/neu gene by siRNA inhibits proliferation and induces apoptosis in HER2/neu-overexpressing breast cancer cells. Neoplasia 6(6):786–795. https://doi.org/10.1593/neo.04313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rossing M, Sørensen CS, Ejlertsen B, Nielsen FC (2019) Whole genome sequencing of breast cancer. Apmis 127(5):303–315

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ferrari A, Vincent-Salomon A, Pivot X, Sertier A-S, Thomas E, Tonon L et al (2016) A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers. Nat Commun 7(1):1–9

    Article  Google Scholar 

  27. Timms JF, White SL, O'Hare MJ, Waterfield MD (2002) Effects of ErbB-2 overexpression on mitogenic signalling and cell cycle progression in human breast luminal epithelial cells. Oncogene 21(43):6573–6586. https://doi.org/10.1038/sj.onc.1205847

    Article  CAS  PubMed  Google Scholar 

  28. Kalkan A, Ozdarendeli A, Bulut Y, Yekeler H, Cobanoglu B, Doymaz MZ (2005) Investigation of Epstein-Barr virus DNA in formalin-fixed and paraffin- embedded breast cancer tissues. Med Princ Pract 14(4):268–271. https://doi.org/10.1159/000085748

    Article  PubMed  Google Scholar 

  29. Preciado MV, Chabay PA, De Matteo EN, Gonzalez P, Grinstein S, Actis A, Gass HD (2005) Epstein-Barr virus in breast carcinoma in Argentina. Arch Pathol Lab Med 129(3):377–381. https://doi.org/10.5858/2005-129-377-evibci

    Article  PubMed  Google Scholar 

  30. Ayee R, Ofori MEO, Wright E, Quaye O (2020) Epstein Barr virus associated lymphomas and epithelia cancers in humans. J Cancer 11(7):1737–1750. https://doi.org/10.7150/jca.37282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tavakoli A, Monavari SH, Solaymani Mohammadi F, Kiani SJ, Armat S, Farahmand M (2020) Association between Epstein-Barr virus infection and gastric cancer: a systematic review and meta-analysis. BMC Cancer 20(1):493. https://doi.org/10.1186/s12885-020-07013-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nkosi D, Sun L, Duke LC, Patel N, Surapaneni SK, Singh M, Meckes DG Jr (2020) Epstein-Barr virus LMP1 promotes syntenin-1- and Hrs-induced extracellular vesicle formation for its own secretion to increase cell proliferation and migration. mBio. https://doi.org/10.1128/mBio.00589-20

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tsai SC, Lin SJ, Chen PW, Luo WY, Yeh TH, Wang HW, Chen CJ, Tsai CH (2009) EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines. Blood 114(1):109–118. https://doi.org/10.1182/blood-2008-12-193375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Arbach H, Viglasky V, Lefeu F, Guinebretière JM, Ramirez V, Bride N et al (2006) Epstein-Barr virus (EBV) genome and expression in breast cancer tissue: effect of EBV infection of breast cancer cells on resistance to paclitaxel (Taxol). J Virol 80(2):845–853. https://doi.org/10.1128/jvi.80.2.845-853.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Guo Q, Qian L, Guo L, Shi M, Chen C, Lv X et al (2010) Transactivators Zta and Rta of Epstein-Barr virus promote G0/G1 to S transition in Raji cells: a novel relationship between lytic virus and cell cycle. Mol Immunol 47(9):1783–1792. https://doi.org/10.1016/j.molimm.2010.02.017

    Article  CAS  PubMed  Google Scholar 

  36. Eichelberg MR, Welch R, Guidry JT, Ali A, Ohashi M, Makielski KR et al (2019) Epstein-Barr virus infection promotes epithelial cell growth by attenuating differentiation-dependent exit from the cell cycle. mBio. https://doi.org/10.1128/mBio.01332-19

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lin JH, Tsai CH, Chu JS, Chen JY, Takada K, Shew JY (2007) Dysregulation of HER2/HER3 signaling axis in Epstein-Barr virus-infected breast carcinoma cells. J Virol 81(11):5705–5713. https://doi.org/10.1128/jvi.00076-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Leong MML, Lung ML (2021) The impact of Epstein–Barr virus infection on epigenetic regulation of host cell gene expression in epithelial and lymphocytic malignancies. Front Oncol 11:629780. https://doi.org/10.3389/fonc.2021.629780

    Article  PubMed  PubMed Central  Google Scholar 

  39. Heather J, Flower K, Isaac S, Sinclair AJ (2009) The Epstein-Barr virus lytic cycle activator Zta interacts with methylated ZRE in the promoter of host target gene egr1. J Gen Virol 90(Pt 6):1450–1454. https://doi.org/10.1099/vir.0.007922-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cayrol C, Flemington EK (1995) Identification of cellular target genes of the Epstein-Barr virus transactivator Zta: activation of transforming growth factor beta igh3 (TGF-beta igh3) and TGF-beta 1. J Virol 69(7):4206–4212. https://doi.org/10.1128/jvi.69.7.4206-4212.1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu P, Speck SH (2003) Synergistic autoactivation of the Epstein-Barr virus immediate-early BRLF1 promoter by Rta and Zta. Virology 310(2):199–206. https://doi.org/10.1016/s0042-6822(03)00145-4

    Article  CAS  PubMed  Google Scholar 

  42. Bonnet M, Guinebretiere JM, Kremmer E, Grunewald V, Benhamou E, Contesso G, Joab I (1999) Detection of Epstein-Barr virus in invasive breast cancers. J Natl Cancer Inst 91(16):1376–1381. https://doi.org/10.1093/jnci/91.16.1376

    Article  CAS  PubMed  Google Scholar 

  43. Wu Y, Wang D, Wei F, Xiong F, Zhang S, Gong Z et al (2020) EBV-miR-BART12 accelerates migration and invasion in EBV-associated cancer cells by targeting tubulin polymerization-promoting protein 1. Faseb j 34(12):16205–16223. https://doi.org/10.1096/fj.202001508R

    Article  CAS  PubMed  Google Scholar 

  44. Bridgewater HE, Date KL, O’Neil JD, Hu C, Arrand JR, Dawson CW, Young LS (2020) The Epstein-Barr virus-encoded EBNA1 protein activates the bone morphogenic protein (BMP) signalling pathway to promote carcinoma cell migration. Pathogens. https://doi.org/10.3390/pathogens9070594

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Jinan Clinical Medical Science and Technology Innovation Plan (Grant numbers 202019071 and 202019172) and the Shandong Province Medical and Health Technology Development Plan (grant number 202106010191).

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Authors and Affiliations

  1. Department of Emergency, Jinan Children’s Hospital, Jinan, 250022, People’s Republic of China

    Hongling Zheng, Wei Zhang, Yan Zhang & Bing Ye

  2. Department of Hematology, Binzhou People’s Hospital, Binzhou, 256600, People’s Republic of China

    Haitao Zhao

  3. Department of Respiratory, Jinan Children’s Hospital, Jinan, 250022, People’s Republic of China

    Yun Zhang

  4. Department of Hematology and Oncology, Jinan Children’s Hospital, Jinan, 250022, People’s Republic of China

    Qingwei Guo

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  1. Hongling Zheng
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  2. Haitao Zhao
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  3. Wei Zhang
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  4. Yan Zhang
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BY and QG contributed to the study conception and design. Material preparation, data collection, and analysis were performed by all authors. The first draft of the manuscript was written by HZ, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bing Ye or Qingwei Guo.

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Zheng, H., Zhao, H., Zhang, W. et al. Epstein–Barr virus immediate-early protein Zta mediates the proliferation and migration of HER2-overexpressing cancer cells. Arch Virol 168, 150 (2023). https://doi.org/10.1007/s00705-023-05774-x

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