Format

Send to

Choose Destination
Oncogene. 2016 Aug 25;35(34):4529-39. doi: 10.1038/onc.2015.512. Epub 2016 Jan 25.

The fibronectin/α3β1 integrin axis serves as molecular basis for keratinocyte invasion induced by βHPV.

Author information

1
Institute of Virology, University of Cologne, Cologne, Germany.
2
Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
3
Barts Cancer Institute, Centre for Tumour Biology, Queen Mary University of London, John Vane Science Centre, London, UK.
4
Center for Experimental Medicine, University Hospital, University of Cologne, Cologne, Germany.

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.

PMID:
26804167
DOI:
10.1038/onc.2015.512
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center