HPV8 field cancerization in a transgenic mouse model Is due to Lrig1+ keratinocyte stem cell expansion

Journal article

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: Lanfredini, S; Olivero, C; Borgogna, C; Calati, F; Powell, K

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Journal of Investigative Dermatology
• Volume: 137
• Issue: 10
• Pages: 2208-2216
• Publication date: 2017-06-06
• Acceptance date: 2017-04-28
• DOI: 10.1016/j.jid.2017.04.039
• EISSN: 1523-1747
• ISSN: 0022-202X
• Pmid: 28595997
• Language: English
• Keywords: cell proliferation; nerve tissue proteins; membrane glycoproteins; neoplasms, experimental; mice, transgenic; keratinocytes; neoplastic stem cells; papillomaviridae; keratosis, actinic; skin neoplasms