1887

Abstract

Epidemiological studies have shown an association between infections by specific betapapillomaviruses, such as human papillomavirus (HPV) types 5 and 8, and cutaneous squamous cell carcinoma (SCC). The role of betapapillomaviruses in the development of cutaneous SCC is, however, still enigmatic. The ability to inhibit UVB-induced apoptosis, as demonstrated for HPV5 , may be important in this respect, as survival of DNA-damaged and mutated cells increases the risk of transformation. The aim of this study was to assess whether inhibition of UVB-induced apoptosis is a general property of betapapillomaviruses and to identify apoptotic factors that are potentially involved in this process. Primary human keratinocytes transduced with E6 and E7 of selected betapapillomaviruses (HPV5, HPV8, HPV15, HPV20, HPV24 and HPV38) were characterized and subjected to UVB irradiation. HPV8- and HPV20-expressing keratinocytes in particular showed fewer signs of apoptosis, as demonstrated by lower levels of active caspase 3, less enzymic caspase activity and less DNA fragmentation. The observed inhibition of UVB-induced apoptosis was mediated by E6 and coincided with reduced steady-state expression of the pro-apoptotic protein Bax. In conclusion, E6 of HPV8 and HPV20 reduces the apoptotic responses upon UVB irradiation when expressed in primary human keratinocytes. Infections with HPV8 and HPV20 may therefore augment the carcinogenic effect of UV radiation and potentially contribute to oncogenic transformation of the skin.

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2008-09-01
2024-03-28
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References

  1. Accardi R., Dong W., Smet A., Cui R., Hautefeuille A., Gabet A. S., Sylla B. S., Gissmann L., Hainaut P., Tommasino M. 2006; Skin human papillomavirus type 38 alters p53 functions by accumulation of ΔNp73. EMBO Rep 7:334–340 [CrossRef]
    [Google Scholar]
  2. Alfandari J., Magal S. S., Jackman A., Schlegel R., Gonen P., Sherman L. 1999; HPV16 E6 oncoprotein inhibits apoptosis induced during serum-calcium differentiation of foreskin human keratinocytes. Virology 257:383–396 [CrossRef]
    [Google Scholar]
  3. Bouwes Bavinck J. N., Feltkamp M. C. 2004; Milk of human kindness? – HAMLET, human papillomavirus, and warts. N Engl J Med 350:2639–2642 [CrossRef]
    [Google Scholar]
  4. Boxman I. L., Russell A., Mulder L. H., Bouwes Bavinck J. N., Ter Schegget J., Green A. 2000; Case–control study in a subtropical Australian population to assess the relation between non-melanoma skin cancer and epidermodysplasia verruciformis human papillomavirus DNA in plucked eyebrow hairs. The Nambour Skin Cancer Prevention Study Group. Int J Cancer 86:118–121 [CrossRef]
    [Google Scholar]
  5. Boxman I. L., Russell A., Mulder L. H., Bouwes Bavinck J. N., Ter Schegget J., Green A. 2001; Association between epidermodysplasia verruciformis-associated human papillomavirus DNA in plucked eyebrow hair and solar keratoses. J Invest Dermatol 117:1108–1112 [CrossRef]
    [Google Scholar]
  6. Caldeira S., de Villiers E. M., Tommasino M. 2000; Human papillomavirus E7 proteins stimulate proliferation independently of their ability to associate with retinoblastoma protein. Oncogene 19:821–826 [CrossRef]
    [Google Scholar]
  7. Caldeira S., Zehbe I., Accardi R., Malanchi I., Dong W., Giarre M., de Villiers E. M., Filotico R., Boukamp P., Tommasino M. 2003; The E6 and E7 proteins of the cutaneous human papillomavirus type 38 display transforming properties. J Virol 77:2195–2206 [CrossRef]
    [Google Scholar]
  8. Daher A., Simbulan-Rosenthal C. M., Rosenthal D. S. 2006; Apoptosis induced by ultraviolet B in HPV-immortalized human keratinocytes requires caspase-9 and is death receptor independent. Exp Dermatol 15:23–34 [CrossRef]
    [Google Scholar]
  9. de Koning M., Quint W., Struijk L., Kleter B., Wanningen P., van Doorn L. J., Weissenborn S. J., Feltkamp M., Ter Schegget J. 2006; Evaluation of a novel highly sensitive, broad-spectrum PCR-reverse hybridization assay for detection and identification of beta-papillomavirus DNA. J Clin Microbiol 44:1792–1800 [CrossRef]
    [Google Scholar]
  10. de Koning M. N., Struijk L., Bavinck J. N., Kleter B., ter Schegget J., Quint W. G., Feltkamp M. C. 2007; Betapapillomaviruses frequently persist in the skin of healthy individuals. J Gen Virol 88:1489–1495 [CrossRef]
    [Google Scholar]
  11. de Villiers E.-M., Fauquet C., Broker T. R., zur Hausen H. 2004; Classification of papillomaviruses. Virology 324:17–27 [CrossRef]
    [Google Scholar]
  12. Dong W., Kloz U., Accardi R., Caldeira S., Tong W. M., Wang Z. Q., Jansen L., Durst M., Sylla B. S. other authors 2005; Skin hyperproliferation and susceptibility to chemical carcinogenesis in transgenic mice expressing E6 and E7 of human papillomavirus type 38. J Virol 79:14899–14908 [CrossRef]
    [Google Scholar]
  13. Feltkamp M. C., Broer R., di Summa F. M., Struijk L., van der Meijden E., Verlaan B. P., Westendorp R. G., ter Schegget J., Spaan W. J., Bouwes Bavinck J. N. 2003; Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer. Cancer Res 63:2695–2700
    [Google Scholar]
  14. Filippova M., Song H., Connolly J. L., Dermody T. S., Duerksen-Hughes P. J. 2002; The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis. J Biol Chem 277:21730–21739 [CrossRef]
    [Google Scholar]
  15. Filippova M., Parkhurst L., Duerkesen-Hughes P. J. 2004; The human papillomavirus 16 E6 protein binds to Fas-associated death domain and protects cells from Fas-triggered apoptosis. J Biol Chem 279:25729–25744 [CrossRef]
    [Google Scholar]
  16. Giampieri S., Storey A. 2004; Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomavirus types 5 and 18. Br J Cancer 90:2203–2209
    [Google Scholar]
  17. Gray L. J., Bjelogrlic P., Appleyard V. C. L., Thompson A. M., Jolly C. E., Lain S., Herrington C. S. 2007; Selective induction of apoptosis by leptomycin B in keratinocytes expressing oncogenes. Int J Cancer 120:2317–2324 [CrossRef]
    [Google Scholar]
  18. Harwood C. A., Proby C. M. 2002; Human papillomaviruses and non-melanoma skin cancer. Curr Opin Infect Dis 15:101–114 [CrossRef]
    [Google Scholar]
  19. Harwood C. A., Spink P. J., Surentheran T., Leigh I. M., Hawke J. L., Proby C. M., Breuer J., McGregor J. M. 1998; Detection of human papillomavirus DNA in PUVA-associated non-melanoma skin cancers. J Invest Dermatol 111:123–127 [CrossRef]
    [Google Scholar]
  20. Harwood C. A., Surentheran T., McGregor J. M., Spink P. J., Leigh I. M., Breuer J., Proby C. M. 2000; Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 61:289–297 [CrossRef]
    [Google Scholar]
  21. Iftner T., Elbel M., Schopp B., Hiller T., Loizou J. I., Caldecott K. W., Stubenrauch F. 2002; Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1. EMBO J 21:4741–4748 [CrossRef]
    [Google Scholar]
  22. 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]
  23. Jackson S., Harwood C., Thomas M., Banks L., Storey A. 2000; Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 14:3065–3073 [CrossRef]
    [Google Scholar]
  24. Karagas M. R., Nelson H. H., Sehr P., Waterboer T., Stukel T. A., Andrew A., Green A. C., Bouwes Bavinck J. N., Perry A. other authors 2006; Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst 98:389–395 [CrossRef]
    [Google Scholar]
  25. 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 [CrossRef]
    [Google Scholar]
  26. Magal S. S., Jackman A., Ish-Shalom S., Botzer L. E., Gonen P., Schlegel R., Sherman L. 2005; Downregulation of Bax mRNA expression and protein stability by the E6 protein of human papillomavirus 16. J Gen Virol 86:611–621 [CrossRef]
    [Google Scholar]
  27. Mansur C. P., Androphy E. J. 1993; Cellular transformation by papillomavirus oncoproteins. Biochim Biophys Acta 1155:323–345
    [Google Scholar]
  28. Masini C., Fuchs P. G., Gabrielli F., Stark S., Sera F., Ploner M., Melchi C. F., Primavera G., Pirchio G. other authors 2003; Evidence for the association of human papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent individuals. Arch Dermatol 139:890–894
    [Google Scholar]
  29. Michel A., Kopp-Schneider A., Zentgraf H., Gruber A. D., de Villiers E. M. 2006; E6/E7 expression of human papillomavirus type 20 (HPV-20) and HPV-27 influences proliferation and differentiation of the skin in UV-irradiated SKH-hr1 transgenic mice. J Virol 80:11153–11164 [CrossRef]
    [Google Scholar]
  30. Mouret S., Sauvaigo S., Peinnequin A., Favier A., Beani J.-C., Leccia M.-T. 2005; E6* oncoprotein expression of human papillomavirus type-16 determines different ultraviolet sensitivity related to glutathione and glutathione peroxidase antioxidant defence. Exp Dermatol 14:401–410 [CrossRef]
    [Google Scholar]
  31. Nishikawa T., Yamashita T., Yamada T., Kobayashi H., Ohkawara A., Fujinaga K. 1991; Tumorigenic transformation of primary rat embryonal fibroblasts by human papillomavirus type 8 E7 gene in collaboration with the activated H-ras gene. Jpn J Cancer Res 82:1340–1343 [CrossRef]
    [Google Scholar]
  32. Ovstebo R., Haug K. B., Lande K., Kierulf P. 2003; PCR-based calibration curves for studies of quantitative gene expression in human monocytes: development and evaluation. Clin Chem 49:425–432 [CrossRef]
    [Google Scholar]
  33. Pfister H., Fuchs P. G., Majewski S., Jablonska S., Pniewska I., Malejczyk M. 2003; High prevalence of epidermodysplasia verruciformis-associated human papillomavirus DNA in actinic keratoses of the immunocompetent population. Arch Dermatol Res 295:273–279 [CrossRef]
    [Google Scholar]
  34. 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]
  35. Schmitt A., Harry J. B., Rapp B., Wettstein F. O., Iftner T. 1994; Comparison of the properties of the E6 and E7 genes of low- and high-risk cutaneous papillomaviruses reveals strongly transforming and high Rb-binding activity for the E7 protein of the low-risk human papillomavirus type 1. J Virol 68:7051–7059
    [Google Scholar]
  36. Simbulan-Rosenthal C. M., Velena A., Veldman T., Schlegel R., Rosenthal D. S. 2002; HPV-16 E6/7 immortalization sensitizes human keratinocytes to ultraviolet B by altering the pathway from caspase-8 to caspase-9-dependent apoptosis. J Biol Chem 277:24709–24716 [CrossRef]
    [Google Scholar]
  37. Steenbergen R. D., de Wilde J., Wilting S. M., Brink A. A., Snijders P. J., Meijer C. J. 2005; HPV-mediated transformation of the anogenital tract. J Clin Virol 32:Suppl. 1S25–S33 [CrossRef]
    [Google Scholar]
  38. Struijk L., Bouwes Bavinck J. N., Wanningen P., Meijden P. Z., Westendorp R. G., ter Schegget J., Feltkamp M. C. 2003; Presence of human papillomavirus DNA in plucked eyebrow hairs is associated with a history of cutaneous squamous cell carcinoma. J Invest Dermatol 121:1531–1535 [CrossRef]
    [Google Scholar]
  39. Thomas M., Banks L. 1998; Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene 17:2943–2954 [CrossRef]
    [Google Scholar]
  40. Thomas M., Banks L. 1999; Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J Gen Virol 80:1513–1517
    [Google Scholar]
  41. Vogt M., Butz K., Dymalla S., Semzow J., Hoppe-Seyler F. 2006; Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein. Oncogene 25:4009–4015 [CrossRef]
    [Google Scholar]
  42. Yamashita T., Segawa K., Fujinaga Y., Nishikawa T., Fujinaga K. 1993; Biological and biochemical activity of E7 genes of the cutaneous human papillomavirus type 5 and 8. Oncogene 8:2433–2441
    [Google Scholar]
  43. zur Hausen H. 2002; Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350 [CrossRef]
    [Google Scholar]
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