Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Prolonged expression of transgenic p16INK4a in the epidermis of mice induced hyperplasia and dysplasia through a paracrine-mediated activation of the Wnt pathway, contributing to the development of premalignant skin lesions.
“In 2020, Azazmeh and colleagues 42 showed that prolonged expression of transgenic p16INK4a in the epidermis of mice induced hyperplasia and dysplasia through a paracrine-mediated activation of the Wnt pathway, contributing to the development of premalignant skin lesions.”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [42]
Intraperitoneal administration of ABT737 eliminated p16-positive cells, inactivated the Wnt pathway, and subsequently suppressed hyperplasia.
“Intraperitoneal administration of the ABT263 analogue, ABT737 (75 mg/kg six times over 9 days after 6 months of Cdk2a induction), eliminated p16-positive cells, inactivated the Wnt pathway, and subsequently suppressed hyperplasia.42”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [42]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 67 · Cited by 57
- Authors
- 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.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Hadassah Medical Center (IL)
- Roswell Park Comprehensive Cancer Center (US)
- Tel Aviv University (IL)
- National and Kapodistrian University of Athens (GR)
- ORCID
- Venue
- Nature Communications
- Published
- 2020-06-01
- Volume
- 11
- Issue
- 1
- Pages
- 2711-2711
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7264228
- OpenAlex
- W3031553099
- Cited by
- 57
- References
- 67
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 6 · 2023: 12 · 2022: 9 · 2021: 14 · 2020: 2
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Israel Science Foundation (1009/13, 2092/18)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p16INK4a, CDKN2A, Wnt signaling, epidermal hyperplasia, keratinocyte proliferation, precancerous lesions, tumor initiation, senescence, senolytics, actinic keratosis, squamous cell carcinoma, paracrine signaling, epidermal papilloma
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Cells, Cultured, Epidermis, Humans, Hyperplasia, Keratosis, Mice, Inbred C57BL, Mice, Transgenic, Papilloma, Keratinocytes, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice, 129 Strain, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
