1887

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Volume 97, Issue 2

The levels of epithelial anchor proteins -catenin and zona occludens-1 are altered by E7 of human papillomaviruses 5 and 8 Free

Abstract

Infection with viruses of the genus , β-human papillomaviruses (β-HPV), is implicated in the development of non-melanoma skin cancer. This was first evidenced for HPV5 and HPV8 in patients with the skin disease epidermodysplasia verruciformis (EV). The relocalization of the junctional bridging proteins β-catenin and zona occludens-1 (ZO-1) from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumour invasion. Here, we report that β-catenin and ZO-1 are strongly upregulated by the E7 oncoproteins of HPV5 and HPV8 in keratinocytes grown in organotypic skin cultures. Although the membrane-tethered form of β-catenin was elevated, no signs of β-catenin activity within the canonical Wnt signalling pathway could be detected. The upregulation of β-catenin and ZO-1 could also be confirmed in the skin of HPV8 transgenic mice as well as in cutaneous squamous cell carcinomas of EV patients. These data provide the first evidence that β-catenin and ZO-1 are direct targets of E7 of the oncogenic β-HPV types 5 and 8. The ability to deregulate these epithelial junction proteins may contribute to the oncogenic potential of these viruses in human skin.

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© 2015 The Authors
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2016-02-01
2024-04-18
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References

  1. Akgül B., Karle P., Adam M., Fuchs P. G., Pfister H. J. 2003; Dual role of tumor suppressor p53 in regulation of DNA replication and oncogene E6-promoter activity of epidermodysplasia verruciformis-associated human papillomavirus type 8. Virology 308:279–290 [View Article][PubMed]
     [Google Scholar]
  2. Akgül B., García-Escudero R., Ghali L., Pfister H. J., Fuchs P. G., Navsaria H., Storey A. 2005; The E7 protein of cutaneous human papillomavirus type 8 causes invasion of human keratinocytes into the dermis in organotypic cultures of skin. Cancer Res 65:2216–2223 [View Article][PubMed]
     [Google Scholar]
  3. Akgül B., Cooke J. C., Storey A. 2006; HPV-associated skin disease. J Pathol 208:165–175 [View Article][PubMed]
     [Google Scholar]
  4. Akgül B., Ghali L., Davies D., Pfister H., Leigh I. M., Storey A. 2007a; HPV8 early genes modulate differentiation and cell cycle of primary human adult keratinocytes. Exp Dermatol 16:590–599 [View Article][PubMed]
     [Google Scholar]
  5. Akgül B., Köse O., Safali M., Purdie K., Cerio R., Proby C., Storey A. 2007b; A distinct variant of Epidermodysplasia verruciformis in a Turkish family lacking EVER1 and EVER2 mutations. J Dermatol Sci 46:214–216 [View Article][PubMed]
     [Google Scholar]
  6. Akgül B., Zigrino P., Frith D., Hanrahan S., Storey A. 2009; Proteomic analysis reveals the actin cytoskeleton as cellular target for the human papillomavirus type 8. Virology 386:1–5 [View Article][PubMed]
     [Google Scholar]
  7. Akgül B., Bauer B., Zigrino P., Storey A., Mauch C., Pfister H. 2011a; Upregulation of lipocalin-2 in human papillomavirus-positive keratinocytes and cutaneous squamous cell carcinomas. J Gen Virol 92:395–401 [View Article][PubMed]
     [Google Scholar]
  8. Akgül B., García-Escudero R., Ekechi C., Steger G., Navsaria H., Pfister H., Storey A. 2011b; The E2 protein of human papillomavirus type 8 increases the expression of matrix metalloproteinase-9 in human keratinocytes and organotypic skin cultures. Med Microbiol Immunol (Berl) 200:127–135 [View Article][PubMed]
     [Google Scholar]
  9. Bello J. O., Nieva L. O., Paredes A. C., Gonzalez A. M., Zavaleta L. R., Lizano M. 2015; Regulation of the WNT/β-catenin signaling pathway by human papillomavirus E6 and E7 oncoproteins. Viruses 7:4734–4755 [View Article][PubMed]
     [Google Scholar]
  10. Beronja S., Janki P., Heller E., Lien W. H., Keyes B. E., Oshimori N., Fuchs E. 2013; RNAi screens in mice identify physiological regulators of oncogenic growth. Nature 501:185–190 [View Article][PubMed]
     [Google Scholar]
  11. Brandner J. M., Zorn-Kruppa M., Yoshida T., Moll I., Beck L. A., De Benedetto A. 2015; Epidermal tight junctions in health and disease. Tissue Barriers 3:e974451 [View Article][PubMed]
     [Google Scholar]
  12. Buitrago-Pérez Á., Hachimi M., Dueñas M., Lloveras B., Santos A., Holguín A., Duarte B., Santiago J. L., Akgül B., other authors. 2012; A humanized mouse model of HPV-associated pathology driven by E7 expression. PLoS One 7:e41743 [View Article][PubMed]
     [Google Scholar]
  13. Burger B., Itin P. H. 2014; Epidermodysplasia verruciformis. Curr Probl Dermatol 45:123–131 [View Article][PubMed]
     [Google Scholar]
  14. Cardoso J. C., Calonje E. 2011; Cutaneous manifestations of human papillomaviruses: a review. Acta Dermatovenerol Alp Pannonica Adriat 20:145–154
     [Google Scholar]
  15. Hintsala H. R., Siponen M., Haapasaari K. M., Karihtala P., Soini Y. 2013; Claudins 1, 2, 3, 4, 5 and 7 in solar keratosis and squamocellular carcinoma of the skin. Int J Clin Exp Pathol 6:2855–2863[PubMed]
     [Google Scholar]
  16. Howley P. M., Pfister H. J. 2015; Beta genus papillomaviruses and skin cancer. Virology 479-480:290–296 [View Article][PubMed]
     [Google Scholar]
  17. Hübbers C. U., Akgül B. 2015; HPV and cancer of the oral cavity. Virulence 6:244–248 [View Article][PubMed]
     [Google Scholar]
  18. Hufbauer M., Biddle A., Borgogna C., Gariglio M., Doorbar J., Storey A., Pfister H., Mackenzie I., Akgül B. 2013; Expression of betapapillomavirus oncogenes increases the number of keratinocytes with stem cell-like properties. J Virol 87:12158–12165 [View Article][PubMed]
     [Google Scholar]
  19. Hufbauer M., Cooke J., van der Horst G. T., Pfister H., Storey A., Akgül B. 2015; Human papillomavirus mediated inhibition of DNA damage sensing and repair drives skin carcinogenesis. Mol Cancer 14:183 [View Article][PubMed]
     [Google Scholar]
  20. Kirschner N., Brandner J. M. 2012; Barriers and more: functions of tight junction proteins in the skin. Ann N Y Acad Sci 1257:158–166 [View Article][PubMed]
     [Google Scholar]
  21. Lazić D., Alborzi F., Marcuzzi G. P., Angel P., Hess J., Pfister H., Akgül B. 2011; Enhanced StefinA and Sprr2 expression during papilloma formation in HPV8 transgenic mice. J Dermatol Sci 62:84–90 [View Article][PubMed]
     [Google Scholar]
  22. Leverrier S., Bergamaschi D., Ghali L., Ola A., Warnes G., Akgül B., Blight K., García-Escudero R., Penna A., other authors. 2007; Role of HPV E6 proteins in preventing UVB-induced release of pro-apoptotic factors from the mitochondria. Apoptosis 12:549–560 [View Article][PubMed]
     [Google Scholar]
  23. Lucs A. V., Abramson A. L., Steinberg B. M. 2014; Overexpressed β-catenin localizes to plasma membrane in respiratory papillomas. J Invest Dermatol 134:1760–1763 [View Article][PubMed]
     [Google Scholar]
  24. Malanchi I., Peinado H., Kassen D., Hussenet T., Metzger D., Chambon P., Huber M., Hohl D., Cano A., other authors. 2008; Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 452:650–653 [View Article][PubMed]
     [Google Scholar]
  25. Morgan R. G., Ridsdale J., Tonks A., Darley R. L. 2014; Factors affecting the nuclear localization of β-catenin in normal and malignant tissue. J Cell Biochem 115:1351–1361 [View Article][PubMed]
     [Google Scholar]
  26. Morita K., Tsukita S., Miyachi Y. 2004; Tight junction-associated proteins (occludin, ZO-1, claudin-1, claudin-4) in squamous cell carcinoma and Bowen's disease. Br J Dermatol 151:328–334 [View Article][PubMed]
     [Google Scholar]
  27. Nindl I., Rösl F. 2008; Molecular concepts of virus infections causing skin cancer in organ transplant recipients. Am J Transplant 8:2199–2204 [View Article][PubMed]
     [Google Scholar]
  28. Patel T., Morrison L. K., Rady P., Tyring S. 2010; Epidermodysplasia verruciformis and susceptibility to HPV. Dis Markers 29:199–206 [View Article][PubMed]
     [Google Scholar]
  29. Polette M., Mestdagt M., Bindels S., Nawrocki-Raby B., Hunziker W., Foidart J. M., Birembaut P., Gilles C. 2007; Beta-catenin and ZO-1: shuttle molecules involved in tumor invasion-associated epithelial-mesenchymal transition processes. Cells Tissues Organs 185:61–65 [View Article][PubMed]
     [Google Scholar]
  30. Pummi K., Malminen M., Aho H., Karvonen S. L., Peltonen J., Peltonen S. 2001; Epidermal tight junctions: ZO-1 and occludin are expressed in mature, developing, and affected skin and in vitro differentiating keratinocytes. J Invest Dermatol 117:1050–1058 [View Article][PubMed]
     [Google Scholar]
  31. Quint K. D., Genders R. E., de Koning M. N., Borgogna C., Gariglio M., Bouwes Bavinck J. N., Doorbar J., Feltkamp M. C. 2015; Human Beta-papillomavirus infection and keratinocyte carcinomas. J Pathol 235:342–354 [View Article][PubMed]
     [Google Scholar]
  32. Rachow S., Zorn-Kruppa M., Ohnemus U., Kirschner N., Vidal-y-Sy S., von den Driesch P., Börnchen C., Eberle J., Mildner M., other authors. 2013; Occludin is involved in adhesion, apoptosis, differentiation and Ca2+-homeostasis of human keratinocytes: implications for tumorigenesis. PLoS One 8:e55116 [View Article][PubMed]
     [Google Scholar]
  33. Schaper I. D., Marcuzzi G. P., Weissenborn S. J., Kasper H. U., Dries V., Smyth N., Fuchs P., Pfister H. 2005; Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8. Cancer Res 65:1394–1400 [View Article][PubMed]
     [Google Scholar]
  34. Schlüter H., Moll I., Wolburg H., Franke W. W. 2007; The different structures containing tight junction proteins in epidermal and other stratified epithelial cells, including squamous cell metaplasia. Eur J Cell Biol 86:645–655 [View Article][PubMed]
     [Google Scholar]
  35. Smalley K. S., Brafford P., Haass N. K., Brandner J. M., Brown E., Herlyn M. 2005; Up-regulated expression of zonula occludens protein-1 in human melanoma associates with N-cadherin and contributes to invasion and adhesion. Am J Pathol 166:1541–1554 [View Article][PubMed]
     [Google Scholar]
  36. Smola S. 2014; Human papillomaviruses and skin cancer. Adv Exp Med Biol 810:192–207[PubMed]
     [Google Scholar]
  37. Staal F. J., van Noort M., Strous G. J., Clevers H. C. 2002; Wnt signals are transmitted through N-terminally dephosphorylated beta-catenin. EMBO Rep 3:63–68 [View Article][PubMed]
     [Google Scholar]
  38. van Noort M., Meeldijk J., van der Zee R., Destree O., Clevers H. 2002; Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem 277:17901–17905 [View Article][PubMed]
     [Google Scholar]
  39. Westphal K., Akgül B., Storey A., Nindl I. 2009; Cutaneous human papillomavirus E7 type-specific effects on differentiation and proliferation of organotypic skin cultures. Cell Oncol 31:213–226[PubMed]
     [Google Scholar]
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The levels of epithelial anchor proteins β-catenin and zona occludens-1 are altered by E7 of human papillomaviruses 5 and 8
J. Gen. Virol. 97, 463 (2016); https://doi.org/10.1099/jgv.0.000363
/content/journal/jgv/10.1099/jgv.0.000363
/content/journal/jgv/10.1099/jgv.0.000363
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