Universität zu Köln

Hasche, Daniel ORCID: 0000-0001-9306-3059, Stephan, Sonja, Braspenning-Wesch, Ilona, Mikulec, Julita, Niebler, Martina, Groene, Hermann-Josef, Flechtenmacher, Christa, Akguel, Baki, Roesl, Frank and Vinzon, Sabrina E. (2017). The interplay of UV and cutaneous papillomavirus infection in skin cancer development. PLoS Pathog., 13 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7374

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Abstract

Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce.H2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored-like in humans-Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hasche, Daniel UNSPECIFIED orcid.org/0000-0001-9306-3059 UNSPECIFIED Stephan, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Braspenning-Wesch, Ilona UNSPECIFIED UNSPECIFIED UNSPECIFIED Mikulec, Julita UNSPECIFIED UNSPECIFIED UNSPECIFIED Niebler, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Groene, Hermann-Josef UNSPECIFIED UNSPECIFIED UNSPECIFIED Flechtenmacher, Christa UNSPECIFIED UNSPECIFIED UNSPECIFIED Akguel, Baki UNSPECIFIED UNSPECIFIED UNSPECIFIED Roesl, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Vinzon, Sabrina E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-213674
DOI:	10.1371/journal.ppat.1006723
Journal or Publication Title:	PLoS Pathog.
Volume:	13
Number:	11
Date:	2017
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7374
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SQUAMOUS-CELL CARCINOMA; MASTOMYS-NATALENSIS PAPILLOMAVIRUS; CYCLOBUTANE PYRIMIDINE DIMERS; ORGAN TRANSPLANT RECIPIENTS; ACTINIC KERATOSES; INDUCED APOPTOSIS; E6 PROTEINS; DNA-DAMAGE; REPAIR; P53 Multiple languages Microbiology; Parasitology; Virology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21367