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

Area of Science:

• Dermatology
• Oncology
• Virology

Background:

• Beta-human papillomaviruses (HPVs) establish latent infections in hair follicle (HF) keratinocyte stem cells.
• In epidermodysplasia verruciformis, β-HPV replication correlates with skin keratosis and squamous cell carcinoma.
• The role of HF stem cells in β-HPV-induced skin carcinogenesis remains to be fully elucidated.

Purpose of the Study:

• To investigate the specific role of HF keratinocyte stem cells in β-HPV-induced skin carcinogenesis.
• To analyze the impact of HPV8 early region expression on HF stem cell populations and epidermal proliferation.

Main Methods:

• Utilized a transgenic mouse model (HPV8tg) expressing the HPV8 early region under the keratin 14 promoter.
• Analyzed HF keratinocyte stem cell populations (Lrig1+, CD34+, LGR5+, LGR6+) for proliferation and expansion.
• Examined p63 isoform expression in HPV8tg skin and compared histology with human skin lesions.

Main Results:

• HPV8tg mice exhibited hyperproliferative epidermis and increased skin thickness.
• Proliferation was significantly increased in the Lrig1+ stem cell population, with a 2.8-fold expansion and 3.8-fold increased colony-forming efficiency.
• Nuclear p63 expression, particularly ΔNp63 isoforms, was observed in Lrig1+ cells and associated with HF infundibulum and interfollicular epidermis.

Conclusions:

• Beta-HPV-induced skin carcinogenesis originates from the hair follicle junctional zone, specifically impacting Lrig1+ keratinocyte stem cells.
• The observed changes in Lrig1+ cells and p63 expression contribute to epidermal hyperplasia and predispose to squamous cell carcinoma.
• Findings suggest a mechanism for β-HPV field cancerization and its link to skin cancer development.