Τίτλος:
Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2020, The Author(s).
Συγγραφείς:
Azazmeh, N.
Assouline, B.
Winter, E.
Ruppo, S.
Nevo, Y.
Maly, A.
Meir, K.
Witkiewicz, A.K.
Cohen, J.
Rizou, S.V.
Pikarsky, E.
Luxenburg, C.
Gorgoulis, V.G.
Ben-Porath, I.
Περιοδικό:
Nature Communications
Εκδότης:
Institute of Geographic Sciences and Natural Resources Research
Λέξεις-κλειδιά:
cyclin dependent kinase inhibitor 2A; Wnt protein; cyclin dependent kinase inhibitor 2A, carcinogen; cell; gene expression; induced response; tumor, actinic keratosis; adult; animal experiment; animal model; animal tissue; Article; carcinogenesis; cell proliferation; controlled study; dysplasia; epidermis; female; hyperplasia; keratinocyte; male; mouse; nonhuman; papilloma; protein expression; skin tumor; tissue structure; Wnt signaling; 129 mouse; animal; C57BL mouse; cell culture; cell transformation; epidermis; genetics; human; hyperplasia; keratosis; metabolism; pathology; transgenic mouse, Animals; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p16; Epidermis; Humans; Hyperplasia; Keratinocytes; Keratosis; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Papilloma; Wnt Signaling Pathway
DOI:
10.1038/s41467-020-16475-3
