Universität zu Köln

Heuser, S., Hufbauer, M., Steiger, J., Marshall, J., Sterner-Kock, A., Mauch, C., Zigrino, P. and Akguel, B. (2016). The fibronectin/alpha 3 beta 1 integrin axis serves as molecular basis for keratinocyte invasion induced by beta HPV. Oncogene, 35 (34). S. 4529 - 4540. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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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 alpha 3-integrin chain. Functional blocking confirmed alpha 3 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 alpha 3 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Heuser, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hufbauer, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Steiger, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marshall, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sterner-Kock, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mauch, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zigrino, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Akguel, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-269100
DOI:	10.1038/onc.2015.512
Journal or Publication Title:	Oncogene
Volume:	35
Number:	34
Page Range:	S. 4529 - 4540
Date:	2016
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPITHELIAL-MESENCHYMAL TRANSITION; HUMAN-PAPILLOMAVIRUS TYPE-8; SQUAMOUS-CELL CARCINOMA; SKIN TUMOR-FORMATION; TRANSGENIC MICE; E-CADHERIN; UP-REGULATION; STEM-CELLS; ORGANOTYPIC CULTURES; EARLY GENES Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26910