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 and Ittai Ben-Porath ()
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Narmen Azazmeh: Institute for Medical Research – Israel-Canada, The Hebrew University–Hadassah Medical School
Benjamin Assouline: Institute for Medical Research – Israel-Canada, The Hebrew University–Hadassah Medical School
Eitan Winter: Info-CORE, Bioinformatics Unit of the I-CORE Computation Center at the Hebrew University and Hadassah
Shmuel Ruppo: Info-CORE, Bioinformatics Unit of the I-CORE Computation Center at the Hebrew University and Hadassah
Yuval Nevo: Info-CORE, Bioinformatics Unit of the I-CORE Computation Center at the Hebrew University and Hadassah
Alexander Maly: Hadassah-Hebrew University Medical Center
Karen Meir: Hadassah-Hebrew University Medical Center
Agnieszka K. Witkiewicz: Roswell Park Cancer Institute
Jonathan Cohen: Sackler Faculty of Medicine Tel Aviv University
Sophia V. Rizou: Medical School, National and Kapodistrian University of Athens
Eli Pikarsky: Hadassah-Hebrew University Medical Center
Chen Luxenburg: Sackler Faculty of Medicine Tel Aviv University
Vassilis G. Gorgoulis: Medical School, National and Kapodistrian University of Athens
Ittai Ben-Porath: Institute for Medical Research – Israel-Canada, The Hebrew University–Hadassah Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.

Date: 2020
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DOI: 10.1038/s41467-020-16475-3

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