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, Cohen Jonathan, Sophia V. Rizou, Eli Pikarsky, Chen Luxenburg, Vassilis G. Gorgoulis, Ittai Ben-Porath*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish
Article number2711
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020

Funding

FundersFunder number
DKFZ-MOST FundCA-161
KIKPE
NKUA-SARG70/3/8916, 70/3/12128
Welfare Foundation for Social & Cultural Sciences
Israel Science Foundation1009/13, 2092/18
Israel Science Foundation
Council for Higher Education

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