title: The fibronectin/α3β1 integrin axis serves as molecular basis for keratinocyte invasion induced by βHPV.
abstract: Organ-transplant-recipients exhibit cancerization of the skin from which multiple human papillomavirus (HPV)-positive squamous cell carcinomas (SCCs) arise. However, the molecular basis for HPV-induced invasion of skin keratinocytes is not known. We generated a transgenic mouse model expressing the E7 oncoprotein of HPV8 in the murine epidermis under the control of the keratin-14 promoter and showed that E7 is carcinogenic in mice. We further showed that both, the E7-expressing keratinocyte and mesenchymal components of the extracellular matrix as critical in eliciting the invasive behavior. E7 expression in basal keratinocytes, grown on fibronectin, led to epithelial-mesenchymal transition mediated by a cadherin switch. E7-positive keratinocytes displayed enhanced EDA-fibronectin expression and secretion and stimulated dermal fibroblasts to express EDA-fibronectin. Deposition of fibronectin was also detected in the peritumoral stroma of HPV8-positive skin SCC. When grown on fibronectin, E7-positive keratinocytes, in particular stem cell-like cells, exhibited increased cell surface levels of the α3-integrin chain. Functional blocking confirmed α3 as a critical molecule sufficient to induce E7-mediated invasion. This mechanistic link is further supported by expression of an E7-mutant, impaired in targeting α3 to the cell surface. These findings highlight the importance of epithelial-extracellular matrix interaction required for keratinocyte invasion and provide further mechanistic evidence for a role of HPV in skin carcinogenesis.
authors.affiliation: Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Heuser
authors.affiliation: Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hufbauer
authors.affiliation: Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Steiger
authors.affiliation: Barts Cancer Institute, Centre for Tumour Biology, Queen Mary University of London, John Vane Science Centre, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Center for Experimental Medicine, University Hospital, University of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sterner-Kock
authors.affiliation: Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Mauch
authors.affiliation: Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Zigrino
authors.affiliation: Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Akgül
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000502:physiology*; D039201:Integrin alpha3beta1 / Q000502:physiology*; D015603:Keratinocytes / Q000473:pathology*; D051379:Mice; D050725:Papillomavirus E7 Proteins / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology / Q000821:virology
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039201:Integrin alpha3beta1; D050725:Papillomavirus E7 Proteins