Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos

Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos

1. Eva M. Briso1,
2. Juan Guinea-Viniegra1,
3. Latifa Bakiri1,
4. Zbigniew Rogon2,
5. Peter Petzelbauer3,
6. Roland Eils2,
7. Ronald Wolf4,
8. Mercedes Rincón5,
9. Peter Angel6 and
10. Erwin F. Wagner1,7

+ Author Affiliations

1. ¹BBVA Foundation-Spanish National Cancer Research Center (CNIO) Cancer Cell Biology Program, CNIO, 28029 Madrid, Spain;
2. ²Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
3. ³Skin and Endothelium Research Division (SERD), Department of Dermatology, Medical University of Vienna, A-1090 Vienna, Austria;
4. ⁴Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany;
5. ⁵Division of Immunobiology, Department of Medicine, University of Vermont, 05405 Burlington, Vermont, USA;
6. ⁶Division of Signal Transduction and Growth Control, DKFZ, DKFZ-Center for Molecular Biology of the University of Heidelberg (ZMBH) Alliance, 69120 Heidelberg, Germany

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.

Keywords

• c-Fos
• AP-1
• inflammation
• cancer
• skin
• CD4 T cell

Footnotes

• ↵7 Corresponding author
  E-mail ewagner@cnio.es
• Supplemental material is available for this article.
• Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.223339.113.

• Received May 29, 2013.
• Accepted August 15, 2013.

• © 2013, Published by Cold Spring Harbor Laboratory Press

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