Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation
Narmen Azazmeh, Benjamin Assouline, Eitan Winter, Shmuel Ruppo, Yuval Nevo, Alexander Maly, Karen Meir, Agnieszka K. Witkiewicz, Jonathan Cohen, Sophia V. Rizou, Eli Pikarsky, Chen Luxenburg, Vassilis G. Gorgoulis, Ittai Ben‐Porath
Abstract
Abstract 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.