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.
Highlights
P16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence
Activity of tumor-suppressive cellular mechanisms is often associated with cell and organismal aging, yet cancer propensity substantially increases with age1–3. p16INK4a, encoded by the CDKN2A gene (p16 hereafter), represents an important link between cancer, cellular responses to stress, and aging. p16 is a central tumor suppressor, which is among the most commonly mutated genes in diverse human malignancies[4,5]
It has been suggested that resident senescent cells can promote tumorigenesis during aging by generating inflammation mediated by cytokine secretion, a feature of senescence known as the senescence-associated secretory phenotype (SASP)[3,19]
Summary
P16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. A precursor of squamous cell carcinoma, p16INK4aexpressing 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. Elimination of p16-expressing senescent cells reduces cancer mortality rates in mice, suggesting that such cells could contribute to tumor development[11] The mechanisms underlying this are not fully known. The high mutation rates of p16 in cutaneous squamous cell carcinoma and other skin malignancies[5,29,30] indicate that it suppresses malignant progression It is unknown whether the activity of p16 in the normal epidermis and in premalignant lesions influences the development of disease. We show that p16 expression in mice and in cultured keratinocytes leads to
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