Cell Type-Specific p38δ Targeting Reveals a Context-, Stage-, and Sex-Dependent Regulation of Skin Carcinogenesis.

Activation and/or upregulated expression of p38 delta are demonstrated in human skin malignancies including cutaneous squamous cell carcinoma, suggesting a role for p38 delta in skin carcinogenesis. We previously reported that mice with germline deletion of the p38 delta gene are significantly protected from chemical skin carcinogenesis. Here, we investigated the effects of cell-selective targeted ablation of p38 delta 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 p38 delta ablation (p38 delta-cKO (increment 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 p38 delta deletion (p38 delta-cKO (increment 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 p38 delta-cKO (increment M) males compared with control wild-type males. Moreover, the percentage of male mice with malignant tumors was decreased in the p38 delta-cKO (increment M) group relative to their wild-type counterparts. Collectively, these results reveal that cell-specific p38 delta targeting modifies susceptibility to chemical skin carcinogenesis in a context-, stage-, and sex-specific manner.