| First Author | Kiss A | Year | 2016 |
| Journal | Mol Carcinog | Volume | 55 |
| Issue | 5 | Pages | 563-74 |
| PubMed ID | 25753147 | Mgi Jnum | J:301877 |
| Mgi Id | MGI:6507248 | Doi | 10.1002/mc.22303 |
| Citation | Kiss A, et al. (2016) Keratinocyte p38delta loss inhibits Ras-induced tumor formation, while systemic p38delta loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin. Mol Carcinog 55(5):563-74 |
| abstractText | p38delta expression and/or activity are increased in human cutaneous malignancies, including invasive squamous cell carcinoma (SCC) and head and neck SCC, but the role of p38delta in cutaneous carcinogenesis has not been well-defined. We have reported that mice with germline loss of p38delta exhibited a reduced susceptibility to skin tumor development compared with wild-type mice in the two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical skin carcinogenesis model. Here, we report that p38delta gene ablation inhibited the growth of tumors generated from v-ras(Ha) -transformed keratinocytes in skin orthografts to nude mice, indicating that keratinocyte-intrinsic p38delta is required for Ras-induced tumorigenesis. Gene expression profiling of v-ras(Ha) -transformed p38delta-null keratinocytes revealed transcriptional changes associated with cellular responses linked to tumor suppression, such as reduced proliferation and increased differentiation, cell adhesion, and cell communications. Notably, a short-term DMBA/TPA challenge, modeling the initial stages of chemical skin carcinogenesis treatment, elicited an enhanced inflammation in p38delta-null skin compared with skin of wild-type mice, as assessed by measuring the expression of pro-inflammatory cytokines, including IL-1beta, IL-6, IL-17, and TNFalpha. Additionally, p38delta-null skin and p38delta-null keratinocytes exhibited increased p38alpha activation and signaling in response to acute inflammatory challenges, suggesting a role for p38alpha in stimulating the elevated inflammatory response in p38delta-null skin during the initial phases of the DMBA/TPA treatment compared with similarly treated p38delta(+/+) skin. Altogether, our results indicate that p38delta signaling regulates skin carcinogenesis not only by keratinocyte cell-autonomous mechanisms, but also by influencing the interaction between between the epithelial compartment of the developing skin tumor and its stromal microenvironment. |
