HPV8 E6 Leads to Lrig1+ Keratinocyte Stem Cell Expansion

The study investigates the role of human papillomavirus 8 (HPV8) in the proliferation and expansion of Lrig1+ keratinocyte stem cells, which are implicated in the development of actinic keratoses (AKs) and cutaneous squamous cell carcinoma (cSCCs). The research found that the E6 gene of HPV8, not E7 as commonly seen in other HPV types, is responsible for the expansion of these stem cells. In HPV8 transgenic mice, expression of E6 led to a broadened hair follicle infundibulum and increased Lrig1+ stem cell proliferation, as evidenced by whole-mount immunofluorescent labeling and flow cytometric analysis. E6-transduced HaCaT keratinocytes showed reduced differentiation, increased migration, and colony-forming efficiency, with higher expression of pSTAT3 and ΔNP63, which are indicative of stem cell expansion. The study also identified that E6 interacts with acetylated p300, a regulator of STAT3 activation, and that disrupting this interaction with an E6K137N mutation or siRNA targeting P300 prevents the development of papilloma or cSCC. This suggests that targeting the E6-p300 interaction could be a potential therapeutic strategy for treating HPV8-related skin lesions.