title: Keratinocyte p38δ loss inhibits Ras-induced tumor formation, while systemic p38δ loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin.
abstract: p38δ 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 p38δ in cutaneous carcinogenesis has not been well-defined. We have reported that mice with germline loss of p38δ 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 p38δ gene ablation inhibited the growth of tumors generated from v-ras(Ha) -transformed keratinocytes in skin orthografts to nude mice, indicating that keratinocyte-intrinsic p38δ is required for Ras-induced tumorigenesis. Gene expression profiling of v-ras(Ha) -transformed p38δ-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 p38δ-null skin compared with skin of wild-type mice, as assessed by measuring the expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-17, and TNFα. Additionally, p38δ-null skin and p38δ-null keratinocytes exhibited increased p38α activation and signaling in response to acute inflammatory challenges, suggesting a role for p38α in stimulating the elevated inflammatory response in p38δ-null skin during the initial phases of the DMBA/TPA treatment compared with similarly treated p38δ(+/+) skin. Altogether, our results indicate that p38δ 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.
authors.affiliation: Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Alexi
authors.initials: A
authors.lastname: Kiss
authors.affiliation: Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Koppel
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Anders
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cataisson
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
authors.affiliation: R. O. Perelman Department of Dermatology, NYU School of Medicine, New York, New York.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Blumenberg
authors.affiliation: Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Efimova
mesh_terms: D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D018631:ras Proteins / Q000235:genetics* / Q000494:pharmacology
chemical_list: D001551:Benz(a)Anthracenes; D048292:Mitogen-Activated Protein Kinase 13; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate
keywords: knockout mice; orthotopic skin grafts; p38α; p38δ; skin inflammation