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.

Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy

“…B-cells can promote SCC development by enabling recruitment of innate immune cells. 58 Furthermore, epidermal activation of c-Fos promotes CD4 + T-cells recruitment that drives epidermal hyperplasia, 59 which when combined with a single DMBA treatment gives rise to extremely aggressive tumors. 59 Moreover, cutaneous infiltration of chronic lymphocytic leukemia predisposes to SCC development, 60 although CD4 + and CD8 + T cells can also confer protection against SCC in Notch-deficient mice.…”

“…58 Furthermore, epidermal activation of c-Fos promotes CD4 + T-cells recruitment that drives epidermal hyperplasia, 59 which when combined with a single DMBA treatment gives rise to extremely aggressive tumors. 59 Moreover, cutaneous infiltration of chronic lymphocytic leukemia predisposes to SCC development, 60 although CD4 + and CD8 + T cells can also confer protection against SCC in Notch-deficient mice. 61 Remarkably, even though adaptive immunity is markedly attenuated in old age, we observe massive recruitment of lymphocytes to the old skin following H-Ras activation.…”

Fos-dependent induction of Chk1 protects osteoblasts from replication stress

“…6 To investigate the mechanisms contributing to the pro-tumorigenic function of Fos in osteoblasts, we used a genetic system where Fos expression is controlled in a switchable fashion upon addition of doxycycline (Dox). 22 We isolated calvarial osteoblasts from Rosa-rtTA; Col…”

Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

“…Deregulated AP-1 expression is found in skin biopsies of patients with inflammatory/proliferative skin diseases, such as psoriasis, and epithelial cancers, such as squamous cell carcinomas (SCCs) (Zenz et al 2005;Guinea-Viniegra et al 2012Briso et al 2013;Eckert et al 2013). The generation of genetically engineered mouse models (GEMMs) has provided insights into the important functions of Jun proteins as well as c-Fos in epidermal homeostasis, inflammation, and cancer (Zenz et al 2003;Meixner et al 2008;Guinea-Viniegra et al 2009, 2012Bakiri et al 2011;Briso et al 2013;Schonthaler et al 2013). In contrast, the functions of the Fos-related proteins Fra-1 and Fra-2 in the epidermis are rather poorly understood.…”