E6 and E7 from Beta Hpv38 Cooperate with Ultraviolet Light in the Development of Actinic Keratosis-Like Lesions and Squamous Cell Carcinoma in Mice

English version České info

Cutaneous beta human papillomavirus (HPV) types appear to be involved in the development of non-melanoma skin cancer (NMSC); however, it is not entirely clear whether they play a direct role. We have previously shown that E6 and E7 oncoproteins from the beta HPV type 38 display transforming activities in several experimental models. To evaluate the possible contribution of HPV38 in a proliferative tissue compartment during carcinogenesis, we generated a new transgenic mouse model (Tg) where HPV38 E6 and E7 are expressed in the undifferentiated basal layer of epithelia under the control of the Keratin 14 (K14) promoter. Viral oncogene expression led to increased cellular proliferation in the epidermis of the Tg animals in comparison to the wild-type littermates. Although no spontaneous formation of tumours was observed during the lifespan of the K14 HPV38 E6/E7-Tg mice, they were highly susceptible to 7,12-dimethylbenz(a)anthracene (DMBA)/12-0-tetradecanoylphorbol-13-acetate (TPA) two-stage chemical carcinogenesis. In addition, when animals were exposed to ultraviolet light (UV) irradiation, we observed that accumulation of p21^WAF1 and cell-cycle arrest were significantly alleviated in the skin of Tg mice as compared to wild-type controls. Most importantly, chronic UV irradiation of Tg mice induced the development of actinic keratosis-like lesions, which are considered in humans as precursors of squamous cell carcinomas (SCC), and subsequently of SCC in a significant proportion of the animals. In contrast, wild-type animals subjected to identical treatments did not develop any type of skin lesions. Thus, the oncoproteins E6 and E7 from beta HPV38 significantly contribute to SCC development in the skin rendering keratinocytes more susceptible to UV-induced carcinogenesis.

Vyšlo v časopise: 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 7(7): e32767. doi:10.1371/journal.ppat.1002125
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002125

Souhrn

Zdroje

1. PisaniPBrayFParkinDM 2002 Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int J Cancer 97 72 81

2. AnanthaswamyHNLoughlinSMCoxPEvansRLUllrichSE 1997 Sunlight and skin cancer: inhibition of p53 mutations in UV-irradiated mouse skin by sunscreens. Nat Med 3 510 514

3. ArmstrongBKKrickerA 2001 The epidemiology of UV induced skin cancer. J Photochem Photobiol B 63 8 18

4. PrestonDSSternRS 1992 Nonmelanoma cancers of the skin. N Engl J Med 327 1649 1662

5. BoyleJMacKieRMBriggsJDJunorBJAitchisonTC 1984 Cancer, warts, and sunshine in renal transplant patients. A case-control study. Lancet 1 702 705

6. KiviatNB 1999 Papillomaviruses in non-melanoma skin cancer: epidemiological aspects. Semin Cancer Biol 9 397 403

7. WalderBKJeremyDCharlesworthJAMacdonaldGJPussellBA 1976 The skin and immunosuppression. Australas J Dermatol 17 94 97

8. WalderBKRobertsonMRJeremyD 1971 Skin cancer and immunosuppression. Lancet 2 1282 1283

9. PfisterH 2003 Chapter 8: human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 31 52 56

10. BouvardVGabetASAccardiRSyllaSBTommasinoM 2006 The cutaneous human papillomavirus types and non-melanoma-skin cancer. Papillomavirus Research: From Natural History to Vaccine and Beyond Caister Academic Press, Norfolk, UK 269 277

11. BerkhoutRJBouwes BavinckJNTer ScheggetJ 2000 Persistence of human papillomavirus DNA in benign and (pre)malignant skin lesions from renal transplant recipients. J Clin Microbiol 38 2087 2096

12. de Jong-TiebenLMBerkhoutRJSmitsHLBouwes BavinckJNVermeerBJ 1995 High frequency of detection of epidermodysplasia verruciformis-associated human papillomavirus DNA in biopsies from malignant and premalignant skin lesions from renal transplant recipients. J Invest Dermatol 105 367 371

13. HarwoodCASurentheranTMcGregorJMSpinkPJLeighIM 2000 Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 61 289 97

14. AnderssonKWaterboerTKirnbauerRSlupetzkyKIftnerT 2008 Seroreactivity to cutaneous human papillomaviruses among patients with nonmelanoma skin cancer or benign skin lesions. Cancer Epidemiol Biomarkers Prev 17 189 195

15. WaterboerTAbeniDSampognaFRotherAMasiniC 2008 Serological association of beta and gamma human papillomaviruses with squamous cell carcinoma of the skin. Br J Dermatol 159 457 459

16. CasabonneDMichaelKMWaterboerTPawlitaMForslundO 2007 A prospective pilot study of antibodies against human papillomaviruses and cutaneous squamous cell carcinoma nested in the Oxford component of the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 121 1862 1868

17. KaragasMRNelsonHHSehrPWaterboerTStukelTA 2006 Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst 98 389 395

18. KaragasMRWaterboerTLiZNelsonHHMichaelKM 2010 Genus beta human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population based case-control study. BMJ 341 c2986

19. BavinckJNNealeREAbeniDEuvrardSGreenAC 2010 Multicenter Study of the Association between Betapapillomavirus Infection and Cutaneous Squamous Cell Carcinoma. Cancer Res 70 9777 9786

20. JacksonSHarwoodCThomasMBanksLStoreyA 2000 Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 14 3065 3073

21. UnderbrinkMPHowieHLBedardKMKoopJIGallowayDA 2008 E6 proteins from multiple human betapapillomavirus types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation. J Virol 82 10408 10417

22. CaldeiraSZehbeIAccardiRMalanchiIDongW 2003 The E6 and E7 proteins of cutaneous human papillomavirus type 38 display transforming properties. J Virol 77 2195 2206

23. GabetASAccardiRBellopedeAPoppSBoukampP 2008 Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38. Faseb J 22 622 632

24. AccardiRDongWSmetACuiRHautefeuilleA 2006 Skin human papillomavirus type 38 alters p53 functions by accumulation of deltaNp73. EMBO Rep 7 334 340

25. SchaperIDMarcuzziGPWeissenbornSJKasperHUDriesV 2005 Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8. Cancer Res 65 1394 1400

26. MarcuzziGPHufbauerMKasperHUWeissenbornSJSmolaS 2009 Spontaneous tumour development in human papillomavirus type 8 E6 transgenic mice and rapid induction by UV-light exposure and wounding. J Gen Virol 90 2855 2864

27. MichelAKopp-SchneiderAZentgrafHGruberADde VilliersEM 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

28. DongWKlozUAccardiRCaldeiraSTongWM 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

29. FuchsE 1995 Keratins and the skin. Annu Rev Cell Dev Biol 11 123 153

30. HelfrichIChenMSchmidtRFurstenbergerGKopp-SchneiderA 2004 Increased incidence of squamous cell carcinomas in Mastomys natalensis papillomavirus E6 transgenic mice during two-stage skin carcinogenesis. J Virol 78 4797 805

31. SongSLiemAMillerJALambertPF 2000 Human papillomavirus types 16 E6 and E7 contribute differently to carcinogenesis. Virology 267 141 150

32. BedardKMUnderbrinkMPHowieHLGallowayDA 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

33. GhittoniRAccardiRHasanUGheitTSyllaB 2010 The biological properties of E6 and E7 oncoproteins from human papillomaviruses. Virus Genes 40 1 13

34. WeissenbornSJNindlIPurdieKHarwoodCProbyC 2005 Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers. J Invest Dermatol 125 93 97

35. IftnerTBierfelderSCsapoZPfisterH 1988 Involvement of human papillomavirus type 8 genes E6 and E7 in transformation and replication. J Virol 62 3655 3661

36. YamashitaTSegawaKFujinagaYNishikawaTFujinagaK 1993 Biological and biochemical activity of E7 genes of the cutaneous human papillomavirus type 5 and 8. Oncogene 8 2433 2441

37. SchmittAHarryJBRappBWettsteinFOIftnerT 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

38. IftnerTFuchsPGPfisterH 1989 Two independently transforming functions of human papillomavirus 8. Curr Top Microbiol Immunol 144 167 173

39. PfefferleRMarcuzziGPAkgulBKasperHUSchulzeF 2008 The human papillomavirus type 8 E2 protein induces skin tumors in transgenic mice. J Invest Dermatol 128 2310 2315

40. AuewarakulPGissmannLCidarreguiA 1994 Targeted expression of the E6 and E7 oncogenes of human papillomavirus type 16 in the epidermis of transgenic mice elicits generalized epidermal hyperplasia involving autocrine factors. Mol Cell Biol 14 8250 8258