1887

Abstract

Cutaneous human papillomavirus type 8 (HPV8) is carcinogenic in patients with epidermodysplasia verruciformis. Transgenic mice with the complete early region (CER) of HPV8 spontaneously developed papillomas, dysplasia and squamous cell carcinomas of the skin. To characterize the role of individual early genes in carcinogenesis, the and / genes were expressed separately in transgenic mice. Nearly all HPV8-E6-positive mice spontaneously developed multifocal tumours, characterized by papillomatosis, hyperkeratosis and varying degrees of epidermal dysplasia. In 6 % of the cases, the tumours became malignant, comparable with HPV8-CER mice. Thus, in the murine epidermis, is the major oncogene necessary and sufficient to induce spontaneous tumour development up to the level of squamous cell carcinoma. To evaluate the synergistic effects of UV light and wound healing, the skin of HPV8 mice was irradiated with UVA/UVB light or wounded with punch biopsies. These treatments induced papillomatosis in HPV8-CER and -E6 mice within 3 weeks. Irradiation with UVA alone did not induce papillomatosis and UVB alone had a weaker effect than UVA/UVB, indicating a synergistic role of UVA in UVB-induced papillomatosis. An HPV8 infection persisting over decades in interaction with sun burns and wound healing processes may be a relevant cause of skin cancer in humans.

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2009-12-01
2024-03-28
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References

  1. Akgül B., Lemme W., García-Escudero R., Storey A., Pfister H. J. 2005; UV-B irradiation stimulates the promoter activity of the high-risk, cutaneous human papillomavirus 5 and 8 in primary keratinocytes. Arch Virol 150:145–151 [CrossRef]
    [Google Scholar]
  2. Andrews D. F., Collins S. J., Reddy A. L. 1990; Absence of the c-Ha-ras codon 61 point mutation in murine solid tumors induced by subcutaneously applied 7,12-dimethylbenzanthracene. Cancer Lett 54:139–145 [CrossRef]
    [Google Scholar]
  3. Asgari M. M., Kiviat N. B., Critchlow C. W., Stern J. E., Argenyi Z. B., Raugi G. J., Berg D., Odland P. B., Hawes S. E., de Villiers E. M. 2008; Detection of human papillomavirus DNA in cutaneous squamous cell carcinoma among immunocompetent individuals. J Invest Dermatol 128:1409–1417 [CrossRef]
    [Google Scholar]
  4. Bailleul B., Brown K., Ramsden M., Akhurst R. J., Fee F., Balmain A. 1989; Chemical induction of oncogene mutations and growth factor activity in mouse skin carcinogenesis. Environ Health Perspect 81:23–27 [CrossRef]
    [Google Scholar]
  5. Bedard K. M., Underbrink M. P., Howie H. L., Galloway D. A. 2008; The E6 oncoproteins from human betapapillomaviruses differentially activate telomerase through an E6AP-dependent mechanism and prolong the lifespan of primary keratinocytes. J Virol 82:3894–3902 [CrossRef]
    [Google Scholar]
  6. Boukamp P. 2005; Non-melanoma skin cancer: what drives tumor development and progression?. Carcinogenesis 26:1657–1667 [CrossRef]
    [Google Scholar]
  7. Capone M., Romagnoli P., Beermann F., MacDonald H. R., van Meerwijk J. P. 2001; Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells. Blood 97:1336–1342 [CrossRef]
    [Google Scholar]
  8. Carraresi L., Tripodi S. A., Mulder L. C., Bertini S., Nuti S., Schuerfeld K., Cintorino M., Bensi G., Rossini M., Mora M. 2001; Thymic hyperplasia and lung carcinomas in a line of mice transgenic for keratin 5-driven HPV16 E6/E7 oncogenes. Oncogene 20:8148–8153 [CrossRef]
    [Google Scholar]
  9. Coussens L. M., Raymond W. W., Bergers G., Laig-Webster M., Behrendtsen O., Werb Z., Caughey G. H., Hanahan D. 1999; Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13:1382–1397 [CrossRef]
    [Google Scholar]
  10. Dahle J., Kvam E., Stokke T. 2005; Bystander effects in UV-induced genomic instability: antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation. J Carcinog 4:11 [CrossRef]
    [Google Scholar]
  11. Dang C., Koehler A., Forschner T., Sehr P., Michael K., Pawlita M., Stockfleth E., Nindl I. 2006; E6/E7 expression of human papillomavirus types in cutaneous squamous cell dysplasia and carcinoma in immunosuppressed organ transplant recipients. Br J Dermatol 155:129–136 [CrossRef]
    [Google Scholar]
  12. de Koning M. N., Weißenborn S. J., Abeni D., Bouwes Bavinck J. N., Euvrard S., Green A. C., Harwood C. A., Naldi L., Neale R. other authors 2009; Prevalence and associated factors of betapapillomavirus infections in individuals without cutaneous squamous cell carcinoma. J Gen Virol 90:1611–1621 [CrossRef]
    [Google Scholar]
  13. Durham S. E., Krishnan K. J., Betts J., Birch-Machin M. A. 2003; Mitochondrial DNA damage in non-melanoma skin cancer. Br J Cancer 88:90–95 [CrossRef]
    [Google Scholar]
  14. Elbel M., Carl S., Spaderna S., Iftner T. 1997; A comparative analysis of the interactions of the E6 proteins from cutaneous and genital papillomaviruses with p53 and E6AP in correlation to their transforming potential. Virology 239:132–149 [CrossRef]
    [Google Scholar]
  15. Favre M., Majewski S., Noszczyk B., Maienfisch F., Pura A., Orth G., Jablonska S. 2000; Antibodies to human papillomavirus type 5 are generated in epidermal repair processes. J Invest Dermatol 114:403–407 [CrossRef]
    [Google Scholar]
  16. Gebhardt C., Riehl A., Durchdewald M., Németh J., Fürstenberger G., Müller-Decker K., Enk A., Arnold B., Bierhaus A. other authors 2008; RAGE signalling sustains inflammation and promotes tumor development. J Exp Med 205:275–285 [CrossRef]
    [Google Scholar]
  17. Giampieri S., Storey A. 2004; Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18. Br J Cancer 90:2203–2209
    [Google Scholar]
  18. Gill R. D., Beltran L., Nettikumara A. N., Harvey R. G., Kootstra A., DiGiovanni J. 1992; Analysis of point mutations in murine c-Ha-ras of skin tumors initiated with dibenz[a,j]anthracene and derivatives. Mol Carcinog 6:53–59 [CrossRef]
    [Google Scholar]
  19. Haller K., Stubenrauch F., Pfister H. 1995; Differentiation-dependent transcription of the epidermodysplasia verruciformis-associated human papillomavirus type 5 in benign lesions. Virology 214:245–255 [CrossRef]
    [Google Scholar]
  20. Halliday G. M., Lyons J. G. 2008; Inflammatory doses of UV may not be necessary for skin carcinogenesis. Photochem Photobiol 84:272–283 [CrossRef]
    [Google Scholar]
  21. Hammes A., Schedl A. 2000; Generation of transgenic mice from plasmids, BACs and YACs. In Mouse Genetics and Transgenics: a Practical Approach pp 217–245Edited by Jackson I. J., Abbott C. M. New York, NY: Oxford University Press;
    [Google Scholar]
  22. Herber R., Liem A., Pitot H., Lambert P. F. 1996; Squamous epithelial hyperplasia and carcinoma in mice transgenic for the human papillomavirus type 16 E7 oncogene. J Virol 70:1873–1881
    [Google Scholar]
  23. Horio T., Miyauchi H., Sindhvananda J., Soh H., Kurokawa I., Asada Y. 1993; The effect of ultraviolet (UVB and PUVA) radiation on the expression of epidermal keratins. Br J Dermatol 128:10–15 [CrossRef]
    [Google Scholar]
  24. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; 2007; Human papillomaviruses. IARC Monogr Eval Carcinog Risks Hum 90:1–636
    [Google Scholar]
  25. Jackson S., Storey A. 2000; E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage. Oncogene 19:592–598 [CrossRef]
    [Google Scholar]
  26. Jackson S., Ghali L., Harwood C., Storey A. 2002; Reduced apoptotic levels in squamous but not basal cell carcinomas correlate with detection of cutaneous human papillomavirus. Br J Cancer 87:319–323 [CrossRef]
    [Google Scholar]
  27. Kiyono T., Hiraiwa A., Ishii S., Takahashi T., Ishibashi M. 1994; Inhibition of p53-mediated transactivation by E6 of type 1, but not type 5, 8, or 47, human papillomavirus of cutaneous origin. J Virol 68:4656–4661
    [Google Scholar]
  28. Konkel D. A., Tilghman S. M., Leder P. 1978; The sequence of the chromosomal mouse β -globin major gene: homologies in capping, splicing and poly(A) sites. Cell 15:1125–1132 [CrossRef]
    [Google Scholar]
  29. Laufer T. M., de Koning J., Markowitz J. S., Lo D., Glimcher L. H. 1996; Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex. Nature 383:81–85 [CrossRef]
    [Google Scholar]
  30. McGargill M. A., Derbinski J. M., Hogquist K. A. 2000; Receptor editing in developing T cells. Nat Immunol 1:336–341 [CrossRef]
    [Google Scholar]
  31. Orth G. 2005; Human papillomaviruses associated with epidermodysplasia verruciformis in non-melanoma skin cancers: guilty or innocent?. J Invest Dermatol 125:xii–xiii
    [Google Scholar]
  32. Orth G. 2006; Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses. Semin Immunol 18:362–374 [CrossRef]
    [Google Scholar]
  33. Pfefferle R., Marcuzzi G. P., Akgül B., Kasper H. U., Schulze F., Haase I., Wickenhauser C., Pfister H. J. 2008; The human papillomavirus type 8 E2 protein induces skin tumors in transgenic mice. J Invest Dermatol 128:2310–2315 [CrossRef]
    [Google Scholar]
  34. Pfister H. 2003; Chapter 8: Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 31:52–56
    [Google Scholar]
  35. Sander C. S., Hamm F., Elsner P., Thiele J. J. 2003; Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br J Dermatol 148:913–922 [CrossRef]
    [Google Scholar]
  36. 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 [CrossRef]
    [Google Scholar]
  37. Scheffner M., Werness B. A., Huibregtse J. M., Levine A. J., Howley P. M. 1990; The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136 [CrossRef]
    [Google Scholar]
  38. Smith M. D., Rees J. L. 1994; Wavelength-specific upregulation of keratin mRNA expression in response to ultraviolet radiation. J Invest Dermatol 102:433–439 [CrossRef]
    [Google Scholar]
  39. Song S., Pitot H. C., Lambert P. F. 1999; The human papillomavirus type 16 E6 gene alone is sufficient to induce carcinomas in transgenic animals. J Virol 73:5887–5893
    [Google Scholar]
  40. Steger G., Pfister H. 1992; In vitro expressed HPV 8 E6 protein does not bind p53. Arch Virol 125:355–360 [CrossRef]
    [Google Scholar]
  41. Underbrink M. P., Howie H. L., Bedard K. M., Koop J. I., Galloway D. A. 2008; E6 proteins from multiple human betapapillomavirus types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation. J Virol 82:10408–10417 [CrossRef]
    [Google Scholar]
  42. Vasioukhin V., Degenstein L., Wise B., Fuchs E. 1999; The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc Natl Acad Sci U S A 96:8551–8556 [CrossRef]
    [Google Scholar]
  43. Wakabayashi Y., Mao J. H., Brown K., Girardi M., Balmain A. 2007; Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature 445:761–765 [CrossRef]
    [Google Scholar]
  44. Weißenborn S. J., De Koning M. N., Wieland U., Quint W. G., Pfister H. J. 2009; Intrafamilial transmission and family-specific spectra of cutaneous betapapillomaviruses. J Virol 83:811–816 [CrossRef]
    [Google Scholar]
  45. Werner S., Munz B. 2000; Suppression of keratin 15 expression by transforming growth factor β in vitro and by cutaneous injury in vivo . Exp Cell Res 254:80–90 [CrossRef]
    [Google Scholar]
  46. Woodworth C. D., Michael E., Smith L., Vijayachandra K., Glick A., Hennings H., Yuspa S. H. 2004; Strain-dependent differences in malignant conversion of mouse skin tumors is an inherent property of the epidermal keratinocyte. Carcinogenesis 25:1771–1778 [CrossRef]
    [Google Scholar]
  47. zur Hausen H. 2000; Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 92:690–698 [CrossRef]
    [Google Scholar]
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