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Human Papillomaviruses and Skin Cancer

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Sunlight, Vitamin D and Skin Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1268))

Abstract

Human papillomaviruses (HPVs) infect squamous epithelia and can induce hyperproliferative lesions. More than 220 different HPV types have been characterized and classified into five different genera. While mucosal high-risk HPVs have a well-established causal role in anogenital carcinogenesis, the biology of cutaneous HPVs is less well understood.

From patients with the rare genetic disorder epidermodysplasia verruciformis (EV) and animal models, evidence is accumulating that cutaneous PV of genus β synergize with ultraviolet (UV) radiation in the development of cutaneous squamous cell carcinoma (cSCC). In 2009, the International Agency for Research on Cancer (IARC) classified the genus β-HPV types 5 and 8 as “possible carcinogenic” biological agents (group 2B) in EV disease. Epidemiological and biological studies indicate that genus β-PV infection may also play a role in UV-mediated skin carcinogenesis in non-EV patients. However, they rather act at early stages of carcinogenesis and become dispensable for the maintenance of the malignant phenotype, compatible with a “hit-and-run” mechanism.

This chapter will give an overview on genus β-PV infections and discuss similarities and differences of cutaneous and genus α mucosal high-risk HPV in epithelial carcinogenesis.

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References

  1. Bernard HU, et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401(1):70–9.

    Article  CAS  PubMed  Google Scholar 

  2. Schiller JT, Lowy DR. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol. 2012;10(10):681–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Patel, C., et al. The impact of 10 years of human papillomavirus (HPV) vaccination in Australia: what additional disease burden will a nonavalent vaccine prevent? Euro Surveill, 2018;23(41).

    Google Scholar 

  4. Jablonska S, Majewski S. Epidermodysplasia verruciformis: immunological and clinical aspects. Curr Top Microbiol Immunol. 1994;186:157–75.

    CAS  PubMed  Google Scholar 

  5. Bouvard V, et al. A review of human carcinogens--Part B: biological agents. Lancet Oncol. 2009;10(4):321–2.

    Article  PubMed  Google Scholar 

  6. Howley PM, Pfister HJ. Beta genus papillomaviruses and skin cancer. Virology. 2015;479-480:290–6.

    Article  CAS  PubMed  Google Scholar 

  7. Venuti A, et al. Cross-talk of cutaneous beta human papillomaviruses and the immune system: determinants of disease penetrance. Philos Trans R Soc Lond Ser B Biol Sci. 2019;374(1773):20180287.

    Article  CAS  Google Scholar 

  8. Smola, S. Immunopathogenesis of HPV-associated cancers and prospects for immunotherapy. Viruses, 2017;9(9).

    Google Scholar 

  9. Lewandowsky F, Lutz W. Ein Fall einer bisher nicht beschriebenen Hauterkrankung (Epidermodysplasia verruciformis). Arch Dermatol Syph. 1922;141:193–203.

    Article  Google Scholar 

  10. Lutzner MA. Epidermodysplasia verruciformis. An autosomal recessive disease characterized by viral warts and skin cancer. A model for viral oncogenesis. Bull Cancer. 1978;65(2):169–82.

    CAS  PubMed  Google Scholar 

  11. Rajagopalan K, et al. Familial epidermodysplasia verruciformis of Lewandowsky and Lutz. Arch Dermatol. 1972;105(1):73–8.

    Article  CAS  PubMed  Google Scholar 

  12. Orth G. Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses. Semin Immunol. 2006;18(6):362–74.

    Article  CAS  PubMed  Google Scholar 

  13. Jablonska S, Milewski B. Information on epidermodysplasia verruciformis Lewandowsky-Lutz; positive results of auto- and heteroinoculation. Dermatologica. 1957;115(1):1–22.

    Article  CAS  PubMed  Google Scholar 

  14. Ruiter M, van Mullem PJ. Behavior of virus in malignant degeneration of skin lesion in epidermodysplasia verruciformis. J Invest Dermatol. 1970;54(4):324–31.

    Article  CAS  PubMed  Google Scholar 

  15. Yabe Y, et al. Virus particles in epidermodysplasia verruciformis with carcinoma. Dermatologica. 1969;139(2):161–4.

    Article  CAS  PubMed  Google Scholar 

  16. Pfister H. Chapter 8: human papillomavirus and skin cancer. J Natl Cancer Inst Monogr. 2003;31:52–6.

    Article  Google Scholar 

  17. Dell'Oste V, et al. High beta-HPV DNA loads and strong seroreactivity are present in epidermodysplasia verruciformis. J Invest Dermatol. 2009;129(4):1026–34.

    Article  CAS  PubMed  Google Scholar 

  18. Borgogna C, et al. Characterization of Beta papillomavirus E4 expression in tumours from Epidermodysplasia Verruciformis patients and in experimental models. Virology. 2012;423(2):195–204.

    Article  CAS  PubMed  Google Scholar 

  19. Weissenborn SJ, et al. Intrafamilial transmission and family-specific spectra of cutaneous beta papillomaviruses. J Virol. 2009;83(2):811–6.

    Article  CAS  PubMed  Google Scholar 

  20. Antonsson A, et al. General acquisition of human papillomavirus infections of skin occurs in early infancy. J Clin Microbiol. 2003;41(6):2509–14.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Antonsson A, et al. The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses. J Virol. 2000;74(24):11636–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Boxman IL, et al. Detection of human papillomavirus DNA in plucked hairs from renal transplant recipients and healthy volunteers. J Invest Dermatol. 1997;108(5):712–5.

    Article  CAS  PubMed  Google Scholar 

  23. Jensen P, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2 Pt 1):177–86.

    Article  CAS  PubMed  Google Scholar 

  24. Weissenborn S, et al. Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients. Med Microbiol Immunol. 2012;201(2):117–25.

    Article  CAS  PubMed  Google Scholar 

  25. Karagas MR, et al. Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst. 2006;98(6):389–95.

    Article  PubMed  Google Scholar 

  26. Karagas MR, et al. Genus beta human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population based case-control study. BMJ. 2010;341:c2986.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Proby CM, et al. A case-control study of beta papillomavirus infection and cutaneous squamous cell carcinoma in organ transplant recipients. Am J Transplant. 2011;11(7):1498–508.

    Article  CAS  PubMed  Google Scholar 

  28. Iannacone MR, et al. Case-control study of cutaneous human papillomaviruses in squamous cell carcinoma of the skin. Cancer Epidemiol Biomark Prev. 2012;21(8):1303–13.

    Article  CAS  Google Scholar 

  29. Weissenborn SJ, et al. Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers. J Invest Dermatol. 2005;125(1):93–7.

    Article  CAS  PubMed  Google Scholar 

  30. Arron ST, et al. Transcriptome sequencing demonstrates that human papillomavirus is not active in cutaneous squamous cell carcinoma. J Invest Dermatol. 2011;131(8):1745–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hasche D, et al. The interplay of UV and cutaneous papillomavirus infection in skin cancer development. PLoS Pathog. 2017;13(11):e1006723.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Viarisio D, et al. Beta HPV38 oncoproteins act with a hit-and-run mechanism in ultraviolet radiation-induced skin carcinogenesis in mice. PLoS Pathog. 2018;14(1):e1006783.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Borgogna C, et al. beta-HPV infection correlates with early stages of carcinogenesis in skin tumors and patient-derived xenografts from a kidney transplant recipient cohort. Front Microbiol. 2018;9:117.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hasche D, Vinzon SE, Rosl F. Cutaneous papillomaviruses and non-melanoma skin cancer: causal agents or innocent bystanders? Front Microbiol. 2018;9:874.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Haller K, Stubenrauch F, Pfister H. Differentiation-dependent transcription of the epidermodysplasia verruciformis-associated human papillomavirus type 5 in benign lesions. Virology. 1995;214(1):245–55.

    Article  CAS  PubMed  Google Scholar 

  36. Muller M, et al. Large scale genotype comparison of human papillomavirus E2-host interaction networks provides new insights for e2 molecular functions. PLoS Pathog. 2012;8(6):e1002761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Oldak M, et al. The human papillomavirus type 8 E2 protein suppresses beta4-integrin expression in primary human keratinocytes. J Virol. 2004;78(19):10738–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Oldak M, et al. Human papillomavirus type 8 E2 protein unravels JunB/Fra-1 as an activator of the beta4-integrin gene in human keratinocytes. J Virol. 2010;84(3):1376–86.

    Article  CAS  PubMed  Google Scholar 

  39. Hadaschik D, et al. The papillomavirus E2 protein binds to and synergizes with C/EBP factors involved in keratinocyte differentiation. J Virol. 2003;77(9):5253–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Podgorska M, et al. Chronic inflammatory microenvironment in epidermodysplasia VERRUCIFORMIS skin lesions: role of the synergism between HPV8 E2 and C/EBPbeta to induce pro-inflammatory S100A8/A9 proteins. Front Microbiol. 2018;9:392.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Oliveira JG, Colf LA, McBride AA. Variations in the association of papillomavirus E2 proteins with mitotic chromosomes. Proc Natl Acad Sci U S A. 2006;103(4):1047–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bentley P, et al. The SMC5/6 complex interacts with the papillomavirus E2 protein and influences maintenance of viral episomal DNA. J Virol. 2018:92(15).

    Google Scholar 

  43. Sakakibara N, Mitra R, McBride AA. The papillomavirus E1 helicase activates a cellular DNA damage response in viral replication foci. J Virol. 2011;85(17):8981–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McBride AA, et al. Hitchhiking on host chromatin: how papillomaviruses persist. Biochim Biophys Acta. 2012;1819(7):820–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. White EA, et al. Comprehensive analysis of host cellular interactions with human papillomavirus E6 proteins identifies new E6 binding partners and reflects viral diversity. J Virol. 2012;86(24):13174–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ruhland A, de Villiers EM. Opposite regulation of the HPV 20-URR and HPV 27-URR promoters by ultraviolet irradiation and cytokines. Int J Cancer. 2001;91(6):828–34.

    Article  CAS  PubMed  Google Scholar 

  47. Akgul B, et al. UV-B irradiation stimulates the promoter activity of the high-risk, cutaneous human papillomavirus 5 and 8 in primary keratinocytes. Arch Virol. 2005;150(1):145–51.. Epub 2004 Oct 5

    Article  CAS  PubMed  Google Scholar 

  48. Oldak M, et al. Differential regulation of human papillomavirus type 8 by interferon regulatory factors 3 and 7. J Virol. 2011;85(1):178–88.

    Article  CAS  PubMed  Google Scholar 

  49. Kim TK, et al. Chemotherapeutic DNA-damaging drugs activate interferon regulatory factor-7 by the mitogen-activated protein kinase kinase-4-cJun NH2-terminal kinase pathway. Cancer Res. 2000;60(5):1153–6.

    CAS  PubMed  Google Scholar 

  50. Takaoka A, Tamura T, Taniguchi T. Interferon regulatory factor family of transcription factors and regulation of oncogenesis. Cancer Sci. 2008;99(3):467–78.. Epub 2008 Jan 9

    Article  CAS  PubMed  Google Scholar 

  51. Ramoz N, et al. A susceptibility locus for epidermodysplasia verruciformis, an abnormal predisposition to infection with the oncogenic human papillomavirus type 5, maps to chromosome 17qter in a region containing a psoriasis locus. J Invest Dermatol. 1999;112(3):259–63.

    Article  CAS  PubMed  Google Scholar 

  52. Ramoz N, et al. Evidence for a nonallelic heterogeneity of epidermodysplasia verruciformis with two susceptibility loci mapped to chromosome regions 2p21-p24 and 17q25. J Invest Dermatol. 2000;114(6):1148–53.

    Article  CAS  PubMed  Google Scholar 

  53. Ramoz N, et al. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet. 2002;32(4):579–81.

    Article  CAS  PubMed  Google Scholar 

  54. Crequer A, et al. EVER2 deficiency is associated with mild T-cell abnormalities. J Clin Immunol. 2013;33(1):14–21.

    Article  CAS  PubMed  Google Scholar 

  55. de Jong SJ, et al. Epidermodysplasia verruciformis: inborn errors of immunity to human beta-papillomaviruses. Front Microbiol. 2018;9:1222.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Keresztes G, Mutai H, Heller S. TMC and EVER genes belong to a larger novel family, the TMC gene family encoding transmembrane proteins. BMC Genomics. 2003;4(1):24.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lazarczyk M, et al. The EVER proteins as a natural barrier against papillomaviruses: a new insight into the pathogenesis of human papillomavirus infections. Microbiol Mol Biol Rev. 2009;73(2):348–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. de Jong SJ, et al. The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to beta-papillomaviruses. J Exp Med. 2018;215(9):2289–310.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Leisner TM, et al. CIB1: a small protein with big ambitions. FASEB J. 2016;30(8):2640–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Laffort C, et al. Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency. Lancet. 2004;363(9426):2051–4.

    Article  CAS  PubMed  Google Scholar 

  61. Bouwes Bavinck JN, et al. Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: a multicenter, prospective cohort study. Am J Transplant. 2018;18(5):1220–30.

    Article  PubMed  Google Scholar 

  62. Borgogna C, et al. Improved detection reveals active beta-papillomavirus infection in skin lesions from kidney transplant recipients. Mod Pathol. 2014;27(8):1101–15.

    Article  CAS  PubMed  Google Scholar 

  63. da Silva LC, et al. Post-ART epidermodysplasia verruciformis in a patient with AIDS. J Int Assoc Physicians AIDS Care (Chic). 2010;9(1):10–4.

    Article  Google Scholar 

  64. Huiras E, et al. Cutaneous manifestations of immune reconstitution inflammatory syndrome. Curr Opin HIV AIDS. 2008;3(4):453–60.

    Article  PubMed  Google Scholar 

  65. Mermet I, et al. Cervical intraepithelial neoplasia associated with epidermodysplasia verruciformis HPV in an HIV-infected patient: a manifestation of immune restoration syndrome. Eur J Dermatol. 2007;17(2):149–52.

    PubMed  Google Scholar 

  66. Michael KM, et al. Seroreactivity of 38 human papillomavirus types in epidermodysplasia verruciformis patients, relatives, and controls. J Invest Dermatol. 2010;130(3):841–8.

    Article  CAS  PubMed  Google Scholar 

  67. Sperling T, et al. Human papillomavirus type 8 interferes with a novel C/EBP beta-mediated mechanism of keratinocyte CCL20 chemokine expression and Langerhans cell migration. PLoS Pathog. 2012;8(7):e1002833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cooper KD, et al. Antigen presentation and T-cell activation in epidermodysplasia verruciformis. J Invest Dermatol. 1990;94(6):769–76.

    Article  CAS  PubMed  Google Scholar 

  69. van Voorst Vader PC, et al. Epidermodysplasia verruciformis: langerhans cells, immunologic effect of retinoid treatment and cytogenetics. Arch Dermatol Res. 1987;279(6):366–73.

    Article  PubMed  Google Scholar 

  70. Stoitzner P, et al. Langerhans cells cross-present antigen derived from skin. Proc Natl Acad Sci U S A. 2006;103(20):7783–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dandie GW, et al. Effects of UV on the migration and function of epidermal antigen presenting cells. Mutat Res. 1998;422(1):147–54.

    Article  CAS  PubMed  Google Scholar 

  72. Charbonnier AS, et al. Macrophage inflammatory protein 3alpha is involved in the constitutive trafficking of epidermal langerhans cells. J Exp Med. 1999;190(12):1755–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Dieu-Nosjean MC, et al. Macrophage inflammatory protein 3alpha is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J Exp Med. 2000;192(5):705–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Le Borgne M, et al. Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. Immunity. 2006;24(2):191–201.

    Article  PubMed  CAS  Google Scholar 

  75. Marthaler AM, et al. Identification of C/EBPalpha as a novel target of the HPV8 E6 protein regulating miR-203 in human keratinocytes. PLoS Pathog. 2017;13(6):e1006406.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Missero C, Antonini D. p63 in squamous cell carcinoma of the skin: more than a stem cell/progenitor marker. J Invest Dermatol. 2017;137(2):280–1.

    Article  CAS  PubMed  Google Scholar 

  77. Tan MJ, et al. Cutaneous beta-human papillomavirus E6 proteins bind Mastermind-like coactivators and repress Notch signaling. Proc Natl Acad Sci U S A. 2012;109(23):E1473–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Meyers JM, Spangle JM, Munger K. The human papillomavirus type 8 E6 protein interferes with NOTCH activation during keratinocyte differentiation. J Virol. 2013;87(8):4762–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Thompson EA, et al. C/EBP alpha expression is downregulated in human nonmelanoma skin cancers and inactivation of C/EBP alpha confers susceptibility to UVB-induced skin squamous cell carcinomas. J Invest Dermatol. 2011;131(6):1339–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Schuster MB, Porse BT. C/EBPalpha: a tumour suppressor in multiple tissues? Biochim Biophys Acta. 2006;1766(1):88–103.

    CAS  PubMed  Google Scholar 

  81. Sinha RP, Hader DP. UV-induced DNA damage and repair: a review. Photochem Photobiol Sci. 2002;1(4):225–36.

    Article  CAS  PubMed  Google Scholar 

  82. Roshan A, Jones PH. Chronic low dose UV exposure and p53 mutation: tilting the odds in early epidermal preneoplasia? Int J Radiat Biol. 2012;88(10):682–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Brash DE, et al. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A. 1991;88(22):10124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Amundson SA, Myers TG, Fornace AJ Jr. Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress. Oncogene. 1998;17(25):3287–99.

    Article  PubMed  Google Scholar 

  85. Ziegler A, et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994;372(6508):773–6.

    Article  CAS  PubMed  Google Scholar 

  86. Ziegler A, et al. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. Proc Natl Acad Sci U S A. 1993;90(9):4216–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Padlewska K, et al. Mutation and abnormal expression of the p53 gene in the viral skin carcinogenesis of epidermodysplasia verruciformis. J Invest Dermatol. 2001;117(4):935–42.

    Article  CAS  PubMed  Google Scholar 

  88. Jackson S, et al. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev. 2000;14(23):3065–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Underbrink MP, et al. E6 proteins from multiple human beta papillomavirus types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation. J Virol. 2008;82(21):10408–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wendel SO, Wallace NA. Loss of genome fidelity: beta HPVs and the DNA damage response. Front Microbiol. 2017;8:2250.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Huibregtse JM, Scheffner M, Howley PM. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J. 1991;10(13):4129–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Huibregtse JM, Scheffner M, Howley PM. Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Mol Cell Biol. 1993;13(2):775–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Steger G, Pfister H. In vitro expressed HPV 8 E6 protein does not bind p53. Arch Virol. 1992;125(1–4):355–60.

    Article  CAS  PubMed  Google Scholar 

  94. Elbel M, et al. 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. 1997;239(1):132–49.

    Article  CAS  PubMed  Google Scholar 

  95. Smola S. Immune deviation and cervical carcinogenesis. Papillomavirus Res. 2019;7:164–7.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Ryckman C, et al. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J Immunol. 2003;170(6):3233–42.

    Article  CAS  PubMed  Google Scholar 

  97. Pfefferle R, et al. The human papillomavirus type 8 E2 protein induces skin tumors in transgenic mice. J Invest Dermatol. 2008;128(9):2310–5.. Epub 2008 Apr 10

    Article  CAS  PubMed  Google Scholar 

  98. Schaper ID, et al. Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8. Cancer Res. 2005;65(4):1394–400.

    Article  CAS  PubMed  Google Scholar 

  99. De Andrea M, et al. Keratinocyte-specific stat3 heterozygosity impairs development of skin tumors in human papillomavirus 8 transgenic mice. Cancer Res. 2010;70(20):7938–48.

    Article  PubMed  CAS  Google Scholar 

  100. Schroer N, et al. Molecular pathobiology of human cervical high-grade lesions: paracrine STAT3 activation in tumor-instructed myeloid cells drives local MMP-9 expression. Cancer Res. 2011;71(1):87–97.

    Article  PubMed  CAS  Google Scholar 

  101. Walch-Ruckheim B, et al. STAT3/IRF1 pathway activation sensitizes cervical cancer cells to chemotherapeutic drugs. Cancer Res. 2016;76(13):3872–83.

    Article  CAS  PubMed  Google Scholar 

  102. Marcuzzi GP, et al. Spontaneous tumour development in human papillomavirus type 8 E6 transgenic mice and rapid induction by UV-light exposure and wounding. J Gen Virol. 2009;90(Pt 12):2855–64.. Epub 2009 Aug 19

    Article  CAS  PubMed  Google Scholar 

  103. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315(26):1650–9.

    Article  CAS  PubMed  Google Scholar 

  105. Viarisio D, et al. E6 and E7 from beta HPV38 cooperate with ultraviolet light in the development of actinic keratosis-like lesions and squamous cell carcinoma in mice. PLoS Pathog. 2011;7(7):e1002125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dong W, et al. Skin hyperproliferation and susceptibility to chemical carcinogenesis in transgenic mice expressing E6 and E7 of human papillomavirus type 38. J Virol. 2005;79(23):14899–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Michel A, et al. 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. 2006;80(22):11153–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hasche D, Rosl F. Mastomys species as model systems for infectious diseases. Viruses. 2019;11(2).

    Google Scholar 

  109. Massimi P, et al. Comparative transforming potential of different human papillomaviruses associated with non-melanoma skin cancer. Virology. 2008;371(2):374–9.

    Article  CAS  PubMed  Google Scholar 

  110. Yamashita T, et al. Biological and biochemical activity of E7 genes of the cutaneous human papillomavirus type 5 and 8. Oncogene. 1993;8(9):2433–41.

    CAS  PubMed  Google Scholar 

  111. Caldeira S, et al. The E6 and E7 proteins of the cutaneous human papillomavirus type 38 display transforming properties. J Virol. 2003;77(3):2195–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Schmitt A, et al. 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. 1994;68(11):7051–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cornet I, et al. Comparative analysis of transforming properties of E6 and E7 from different beta human papillomavirus types. J Virol. 2012;86(4):2366–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Brimer N, et al. Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling. Oncogene. 2012;31(43):4639–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rozenblatt-Rosen O, et al. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature. 2012;487(7408):491–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Meyers JM, Spangle JM, Munger K. The HPV8 E6 protein interferes with NOTCH activation during keratinocyte differentiation. J Virol. 2013;87:4762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nicolas M, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003;33(3):416–21.

    Article  CAS  PubMed  Google Scholar 

  118. Scheffner M, et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990;63(6):1129–36.

    Article  CAS  PubMed  Google Scholar 

  119. Scheffner M, et al. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993;75(3):495–505.

    Article  CAS  PubMed  Google Scholar 

  120. Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990;248(4951):76–9.

    Article  CAS  PubMed  Google Scholar 

  121. Giampieri S, Storey A. Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18. Br J Cancer. 2004;90(11):2203–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Muschik D, et al. Cutaneous HPV23 E6 prevents p53 phosphorylation through interaction with HIPK2. PLoS One. 2011;6(11):e27655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Accardi R, et al. Skin human papillomavirus type 38 alters p53 functions by accumulation of deltaNp73. EMBO Rep. 2006;7(3):334–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bedard KM, et al. The E6 oncoproteins from human beta papillomaviruses differentially activate telomerase through an E6AP-dependent mechanism and prolong the lifespan of primary keratinocytes. J Virol. 2008;82(8):3894–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gabet AS, et al. Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38. FASEB J. 2008;22(2):622–32.

    Article  CAS  PubMed  Google Scholar 

  126. Muller-Schiffmann A, Beckmann J, Steger G. The E6 protein of the cutaneous human papillomavirus type 8 can stimulate the viral early and late promoters by distinct mechanisms. J Virol. 2006;80(17):8718–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Howie HL, et al. Beta-HPV 5 and 8 E6 promote p300 degradation by blocking AKT/p300 association. PLoS Pathog. 2011;7(8):e1002211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Muench P, et al. Cutaneous papillomavirus E6 proteins must interact with p300 and block p53-mediated apoptosis for cellular immortalization and tumorigenesis. Cancer Res. 2010;70(17):6913–24.

    Article  CAS  PubMed  Google Scholar 

  129. Wallace NA, et al. HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. PLoS Pathog. 2012;8(7):e1002807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. White EA, et al. Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses. Proc Natl Acad Sci U S A. 2012;109(5):E260–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Buitrago-Perez A, et al. A humanized mouse model of HPV-associated pathology driven by E7 expression. PLoS One. 2012;7(7):e41743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Shephard P, et al. Myofibroblast differentiation is induced in keratinocyte-fibroblast co-cultures and is antagonistically regulated by endogenous transforming growth factor-beta and interleukin-1. Am J Pathol. 2004;164(6):2055–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Habig M, et al. E7 proteins from high- and low-risk human papillomaviruses bind to TGF-beta-regulated Smad proteins and inhibit their transcriptional activity. Arch Virol. 2006;151(10):1961–72.

    Article  CAS  PubMed  Google Scholar 

  134. Lee DK, et al. The human papilloma virus E7 oncoprotein inhibits transforming growth factor-beta signaling by blocking binding of the Smad complex to its target sequence. J Biol Chem. 2002;277(41):38557–64.

    Article  CAS  PubMed  Google Scholar 

  135. Smola-Hess S, et al. Expression of membrane type 1 matrix metalloproteinase in papillomavirus-positive cells: role of the human papillomavirus (HPV) 16 and HPV8 E7 gene products. J Gen Virol. 2005;86(Pt 5):1291–6.

    Article  CAS  PubMed  Google Scholar 

  136. Akgul B, et al. The E7 protein of cutaneous human papillomavirus type 8 causes invasion of human keratinocytes into the dermis in organotypic cultures of skin. Cancer Res. 2005;65(6):2216–23.

    Article  PubMed  Google Scholar 

  137. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Institute of Virology Saarland University Medical Center, Homburg/Saar, Germany

    Sigrun Smola

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  1. Center for Clinical and Experimental Photodermatology and Department of Dermatology, Saarland University Medical Center, Homburg, Germany

    Jörg Reichrath

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Smola, S. (2020). Human Papillomaviruses and Skin Cancer. In: Reichrath, J. (eds) Sunlight, Vitamin D and Skin Cancer. Advances in Experimental Medicine and Biology, vol 1268. Springer, Cham. https://doi.org/10.1007/978-3-030-46227-7_10

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