Department of Anatomy & Cell Biology, The George Washington University School of Medicine and Health Sciences, 2300 I Street NW, Ross Hall 550, Washington, DC 20037, USA.
The George Washington Cancer Center, 800 22nd Street NW, Science and Engineering Hall 8160, Washington, DC 20052, USA.
Int J Mol Sci. 2019 Mar 27;20(7):1532. doi: 10.3390/ijms20071532.
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()anthracene (DMBA)/12--tetradecanoylphorbol-13-acetate (TPA) chemical mouse skin carcinogenesis model. Conditional keratinocyte-specific p38δ ablation (p38δ-cKO) 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) 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 males compared with control wild-type males. Moreover, the percentage of male mice with malignant tumors was decreased in the p38δ-cKO 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.
p38δ 的激活和/或表达上调已在包括皮肤鳞状细胞癌在内的人类皮肤恶性肿瘤中得到证实，提示 p38δ 在皮肤癌变中起作用。我们之前报道过，p38δ 基因种系缺失的小鼠对化学性皮肤致癌作用具有显著的保护作用。在这里，我们研究了角质形成细胞和免疫（髓样）细胞中 p38δ 的细胞选择性靶向消融对二阶段 7,12-二甲基苯并（a）蒽（DMBA）/12-O-十四烷酰佛波醇-13-乙酸酯（TPA）化学性小鼠皮肤致癌模型中皮肤肿瘤发展的影响。条件性角质形成细胞特异性 p38δ 消融（p38δ-cKO）并不影响化学诱导的皮肤肿瘤的潜伏期、发生率或多发性，但在 TPA 促进阶段导致雌性肿瘤体积增大，并与野生型相比，雄性和雌性的恶性进展减少。相比之下，条件性髓样细胞特异性 p38δ 缺失（p38δ-cKO）抑制了雄性而非雌性小鼠的 DMBA/TPA 诱导的皮肤肿瘤发生。因此，与对照野生型雄性相比，p38δ-cKO 雄性的肿瘤起始延迟，肿瘤发生率、多发性和体积减少。此外，p38δ-cKO 组中具有恶性肿瘤的雄性小鼠的百分比相对于其野生型对照减少。总之，这些结果表明，细胞特异性 p38δ 靶向以上下文、阶段和性别特异性的方式改变对化学性皮肤致癌作用的易感性。
