Abstract
Activation and/or upregulated expression of p38δ are demonstrated in human skin malignancies including cutaneous squamous cell carcinoma, suggesting a role for p38δ in skin carcinogenesis. We previously reported that mice with germline deletion of the p38δ gene are significantly protected from chemical skin carcinogenesis. Here, we investigated the effects of cell-selective targeted ablation of p38δ in keratinocytes and in immune (myeloid) cells on skin tumor development in a two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical mouse skin carcinogenesis model. Conditional keratinocyte-specific p38δ ablation (p38δ-cKO∆K ) did not influence the latency, incidence, or multiplicity of chemically-induced skin tumors, but led to increased tumor volume in females during the TPA promotion stage, and reduced malignant progression in males and females relative to their wild-type counterparts. In contrast, conditional myeloid cell-specific p38δ deletion (p38δ-cKO∆M ) inhibited DMBA/TPA-induced skin tumorigenesis in male but not female mice. Thus, tumor onset was delayed, and tumor incidence, multiplicity, and volume were reduced in p38δ-cKO∆M males compared with control wild-type males. Moreover, the percentage of male mice with malignant tumors was decreased in the p38δ-cKO∆M group relative to their wild-type counterparts. Collectively, these results reveal that cell-specific p38δ targeting modifies susceptibility to chemical skin carcinogenesis in a context-, stage-, and sex-specific manner.
Original language | English (US) |
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Article number | 1532 |
Journal | International journal of molecular sciences |
Volume | 20 |
Issue number | 7 |
DOIs | |
State | Published - Apr 1 2019 |
Funding
This research was funded by NIH grant R01 CA133038 (to T.E.), and by funds from the Division of Dermatology, Washington University School of Medicine, and from the Department of Anatomy & Cell Biology, The GWU School of Medicine and Health Sciences. Acknowledgments: We are grateful to Romeo Ricci (Institute of Genetics and Cellular Biology (IGBMC), University of Strasbourg) for generously supplying p38δflox/flox mice, with the kind permission from Boehringer Ingelheim Pharmaceuticals Inc. We thank Mary Ann Stepp (GWU) for generously allowing the use of microscopic imaging system in her laboratory, and Jaclyn Andricovich and Alexandros Tzatsos (GWU) for kindly sharing reagents and equipment. Funding: This research was funded by NIH grant R01 CA133038 (to T.E.), and by funds from the Division of Dermatology, Washington University School of Medicine, and from the Department of Anatomy & Cell Biology, The GWU School of Medicine and Health Sciences.
Keywords
- Conditional knockout mice
- Keratinocytes
- Myeloid cells
- P38δ/MAPK13
- Skin carcinogenesis
ASJC Scopus subject areas
- Molecular Biology
- Spectroscopy
- Catalysis
- Inorganic Chemistry
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry