HPV8 Field Cancerization in a Transgenic Mouse Model Is due to Lrig1+ Keratinocyte Stem Cell Expansion.

Abstract

β-Human papillomaviruses (HPVs) cause near ubiquitous latent skin infection within long-lived hair follicle (HF) keratinocyte stem cells. In patients with epidermodysplasia verruciformis, β-HPV viral replication is associated with skin keratosis and cutaneous squamous cell carcinoma. To determine the role of HF keratinocyte stem cells in β-HPV-induced skin carcinogenesis, we utilized a transgenic mouse model in which the keratin 14 promoter drives expression of the entire HPV8 early region (HPV8tg). HPV8tg mice developed thicker skin in comparison with wild-type littermates consistent with a hyperproliferative epidermis. HF keratinocyte proliferation was evident within the Lrig1+ keratinocyte stem cell population (69 vs. 55%, P < 0.01, n = 7), and not in the CD34+, LGR5+, and LGR6+ keratinocyte stem cell populations. This was associated with a 2.8-fold expansion in Lrig1+ keratinocytes and 3.8-fold increased colony-forming efficiency. Consistent with this, we observed nuclear p63 expression throughout this population and the HF infundibulum and adjoining interfollicular epidermis, associated with a switch from p63 transcriptional activation isoforms to ΔNp63 isoforms in HPV8tg skin. Epidermodysplasia verruciformis keratosis and in some cases actinic keratoses demonstrated similar histology associated with β-HPV reactivation and nuclear p63 expression within the HF infundibulum and perifollicular epidermis. These findings would suggest that β-HPV field cancerization arises from the HF junctional zone and predispose to squamous cell carcinoma.

• Authors: Simone Lanfredini, Carlotta Olivero, Cinzia Borgogna, Federica Calati, Kathryn Powell, Kelli-Jo Davies, Marco De Andrea, Sarah Harries, Hiu Kwan Carolyn Tang, Herbert Pfister, Marisa Gariglio, Girish K Patel
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 137 Issue 10 Pg. 2208-2216 (10 2017) ISSN: 1523-1747 [Electronic] United States
• PMID: 28595997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Lrig1 protein, mouse
• Membrane Glycoproteins
• Nerve Tissue Proteins

Topics

• Animals
• Cell Proliferation
• Keratinocytes (metabolism, pathology)
• Keratosis, Actinic (metabolism, pathology)
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Transgenic
• Neoplasms, Experimental
• Neoplastic Stem Cells (metabolism, pathology)
• Nerve Tissue Proteins (metabolism)
• Papillomaviridae
• Skin Neoplasms (metabolism, pathology)