Abstract |
Human papillomaviruses (HPV) of genus Betapapillomavirus (betaPV) are associated with nonmelanoma skin cancer development in epidermodysplasia verruciformis (EV) and immunosuppressed patients. Epidemiological and molecular studies suggest a carcinogenic activity of betaPV during early stages of cancer development. Since viral oncoproteins delay and perturb keratinocyte differentiation, they may have the capacity to either retain or confer a "stem cell-like" state on oncogene-expressing cells. The aim of this study was to determine (i) whether betaPV alters the expression of cell surface markers, such as CD44 and epithelial cell adhesion molecule ( EpCAM), that have been associated with epithelial stemness, and (ii) whether this confers functional stem cell-like properties to human cutaneous keratinocytes. Fluorescence-activated cell sorter (FACS) analysis revealed an increase in the number of cells with high CD44 and EpCAM expression in keratinocyte cultures expressing HPV type 8 (HPV8) oncogenes E2, E6, and E7. Particularly through E7 expression, a distinct increase in clonogenicity and in the formation and size of tumor spheres was observed, accompanied by reduction of the epithelial differentiation marker Calgranulin B. These stem cell-like properties could be attributed to the pool of CD44(high) EpCAM(high) cells, which was increased within the E7 cultures of HPV5, -8, and -20. Enhanced EpCAM levels were present in organotypic skin cultures of primary keratinocytes expressing E7 of the oncogenic HPV types HPV5, -8, and -16 and in clinical samples from EV patients. In conclusion, our data show that betaPV may increase the number of stem cell-like cells present during early carcinogenesis and thus enable the persistence and accumulation of DNA damage necessary to generate malignant stem cells.
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Authors | Martin Hufbauer, Adrian Biddle, Cinzia Borgogna, Marisa Gariglio, John Doorbar, Alan Storey, Herbert Pfister, Ian Mackenzie, Baki Akgül |
Journal | Journal of virology
(J Virol)
Vol. 87
Issue 22
Pg. 12158-65
(Nov 2013)
ISSN: 1098-5514 [Electronic] United States |
PMID | 24006432
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antigens, Neoplasm
- CD44 protein, human
- Cell Adhesion Molecules
- EPCAM protein, human
- Epithelial Cell Adhesion Molecule
- Hyaluronan Receptors
- Oncogene Proteins, Viral
- RNA, Messenger
- oncogene protein E7, Human papillomavirus type 8
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Topics |
- Antigens, Neoplasm
(genetics, metabolism)
- Apoptosis
- Betapapillomavirus
(pathogenicity)
- Blotting, Western
- Cell Adhesion Molecules
(genetics, metabolism)
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Colony-Forming Units Assay
- Epithelial Cell Adhesion Molecule
- Fluorescent Antibody Technique
- Humans
- Hyaluronan Receptors
(genetics, metabolism)
- Keratinocytes
(metabolism, pathology, virology)
- Oncogene Proteins, Viral
(genetics, metabolism)
- Papillomavirus Infections
(metabolism, pathology, virology)
- RNA, Messenger
(genetics)
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Skin Diseases
(metabolism, pathology, virology)
- Stem Cells
(metabolism, pathology, virology)
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