title: Deletion of epidermal Rac1 inhibits HPV-8 induced skin papilloma formation and facilitates HPV-8- and UV-light induced skin carcinogenesis.
abstract: Overexpression and increased activity of the small Rho GTPase Rac1 has been linked to squamous cell carcinoma of the epidermis and mucosa in humans. Targeted deletion of Rac1 or inhibition of Rac1 activity in epidermal keratinocytes reduced papilloma formation in a chemical skin carcinogenesis mouse model. However, a potential role of Rac1 in HPV- and UV-light induced skin carcinogenesis has not been investigated so far, solar UV radiation being an important carcinogen to the skin.To investigate this, we deleted Rac1 or modulated its activity in mice with transgenic expression of Human papilloma virus type-8 (HPV-8) in epidermal keratinocytes. Our data show that inhibition or deletion of Rac1 results in reduced papilloma formation upon UV-irradiation with a single dose, whereas constitutive activation of Rac1 strongly increases papilloma frequency in these mice. Surprisingly, we observed that, upon chronic UV-irradiation, the majority of mice with transgenic expression of HPV-8 and epidermis specific Rac1 deletion developed squamous cell carcinomas. Taken together, our data show that Rac1 exerts a dual role in skin carcinogenesis: its activation is, on one hand, required for HPV-8- and UV-light induced papilloma formation but, on the other, suppresses the development of squamous cell carcinomas.
authors: Department of Dermatology, University of Cologne, Cologne, 50937, Germany.
authors: Jayesh
authors: J
authors: Deshmukh
authors: Department of Dermatology, University of Cologne, Cologne, 50937, Germany.
authors: Ruth
authors: R
authors: Pofahl
authors: Institute of Virology, University of Cologne, Cologne, 50935, Germany.
authors: Herbert
authors: H
authors: Pfister
authors: Department of Dermatology, University of Cologne, Cologne, 50937, Germany.
authors: Ingo
authors: I
authors: Haase
mesh_terms: D000818:Animals; D002273:Carcinogens; D004817:Epidermis / Q000378:metabolism*; D017353:Gene Deletion; D006657:Histones / Q000737:chemistry; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics; D010212:Papilloma / Q000235:genetics* / Q000821:virology; D027383:Papillomaviridae; D010641:Phenotype; D012871:Skin Diseases / Q000235:genetics* / Q000821:virology; D012878:Skin Neoplasms / Q000235:genetics* / Q000821:virology; D014466:Ultraviolet Rays / Q000009:adverse effects; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: D002273:Carcinogens; D006657:Histones; D009479:Neuropeptides; D020830:rac1 GTP-Binding Protein; C484602:Rac1 protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: HPV-8; Rac1; SCC; UV (Ultraviolet) light; skin cancer