Chronic expression of p16(INK4a) in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

p16(INK4a) (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16(INK4a) accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16(INK4a) in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16(INK4a) expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16(INK4a) expression, and Wnt inhibition suppresses p16(INK4a)-induced hyperplasia. Senolytic treatment reduces p16(INK4a)-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16(INK4a)-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16(INK4a) expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.