title: E6 and E7 from beta HPV38 cooperate with ultraviolet light in the development of actinic keratosis-like lesions and squamous cell carcinoma in mice.
abstract: 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.
authors.affiliation: DKFZ, Heidelberg, Germany.
authors.forename: Daniele
authors.initials: D
authors.lastname: Viarisio
authors.forename: Karin
authors.initials: K
authors.lastname: Mueller-Decker
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kloz
authors.forename: Birgit
authors.initials: B
authors.lastname: Aengeneyndt
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Tarik
authors.initials: T
authors.lastname: Gheit
authors.forename: Christa
authors.initials: C
authors.lastname: Flechtenmacher
authors.forename: Lutz
authors.initials: L
authors.lastname: Gissmann
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects / Q000494:pharmacology; D052685:Alphapapillomavirus; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D055623:Keratosis, Actinic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis* / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D002273:Carcinogens; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009856:Oncogene Proteins, Viral; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate