E6 and E7 from beta HPV38 cooperate with ultraviolet light in the development of actinic keratosis-like lesions and squamous cell carcinoma in mice

• Published in: PLoS pathogens Vol. 7; no. 7; p. e1002125
• Main Authors: Viarisio, Daniele, Mueller-Decker, Karin, Kloz, Ulrich, Aengeneyndt, Birgit, Kopp-Schneider, Annette, Gröne, Hermann-Josef, Gheit, Tarik, Flechtenmacher, Christa, Gissmann, Lutz, Tommasino, Massimo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2011; Public Library of Science (PLoS)
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - adverse effects; 9,10-Dimethyl-1,2-benzanthracene - pharmacology; Actinic keratosis; Alphapapillomavirus; Animals; Biology; Carcinogens - pharmacology; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - virology; Cervical cancer; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Epidermis - metabolism; Epidermis - pathology; Epidermis - virology; Experiments; Health aspects; Human papillomavirus; Humans; Keratinocytes - metabolism; Keratinocytes - pathology; Keratinocytes - virology; Keratosis, Actinic - genetics; Keratosis, Actinic - metabolism; Keratosis, Actinic - pathology; Keratosis, Actinic - virology; Medicine; Mice; Mice, Transgenic; Oncogene Proteins, Viral - biosynthesis; Oncogene Proteins, Viral - genetics; Papillomavirus Infections - genetics; Papillomavirus Infections - metabolism; Papillomavirus Infections - pathology; Papillomaviruses; Physiological aspects; Risk factors; Rodents; Skin cancer; Skin Neoplasms - etiology; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin Neoplasms - virology; Squamous cell carcinoma; Statistical analysis; Studies; Tetradecanoylphorbol Acetate - adverse effects; Tetradecanoylphorbol Acetate - pharmacology; Tumor proteins; Tumors; Ultraviolet radiation; Ultraviolet Rays - adverse effects; Saudi Arabia; France; Germany
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1002125

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.