title: Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos.
abstract: Skin squamous cell carcinomas (SCCs) are the second most prevalent skin cancers. Chronic skin inflammation has been associated with the development of SCCs, but the contribution of skin inflammation to SCC development remains largely unknown. In this study, we demonstrate that inducible expression of c-fos in the epidermis of adult mice is sufficient to promote inflammation-mediated epidermal hyperplasia, leading to the development of preneoplastic lesions. Interestingly, c-Fos transcriptionally controls mmp10 and s100a7a15 expression in keratinocytes, subsequently leading to CD4 T-cell recruitment to the skin, thereby promoting epidermal hyperplasia that is likely induced by CD4 T-cell-derived IL-22. Combining inducible c-fos expression in the epidermis with a single dose of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) leads to the development of highly invasive SCCs, which are prevented by using the anti-inflammatory drug sulindac. Moreover, human SCCs display a correlation between c-FOS expression and elevated levels of MMP10 and S100A15 proteins as well as CD4 T-cell infiltration. Our studies demonstrate a bidirectional cross-talk between premalignant keratinocytes and infiltrating CD4 T cells in SCC development. Therefore, targeting inflammation along with the newly identified targets, such as MMP10 and S100A15, represents promising therapeutic strategies to treat SCCs.
authors.affiliation: BBVA Foundation-Spanish National Cancer Research Center (CNIO) Cancer Cell Biology Program, CNIO, 28029 Madrid, Spain;
authors.forename: Eva M
authors.initials: EM
authors.lastname: Briso
authors.forename: Juan
authors.initials: J
authors.lastname: Guinea-Viniegra
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Rogon
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Ronald
authors.initials: R
authors.lastname: Wolf
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincón
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001551:Benz(a)Anthracenes; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002294:Carcinoma, Squamous Cell / Q000503:physiopathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010212:Papilloma / Q000139:chemically induced / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000503:physiopathology*
chemical_list: D001551:Benz(a)Anthracenes; D016760:Proto-Oncogene Proteins c-fos; C046810:7,12-dihydroxymethylbenz(a)anthracene; D053506:Matrix Metalloproteinase 10
keywords: AP-1; CD4 T cell; c-Fos; cancer; inflammation; skin
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