Journal
EMBO MOLECULAR MEDICINE
Volume 6, Issue 7, Pages 970-983Publisher
WILEY
DOI: 10.15252/emmm.201303541
Keywords
apoptosis; inflammation; mouse models of cancer; NF-kappa B signalling; skin carcinogenesis
Categories
Funding
- Deutsche Krebshilfe [110302]
- Deutsche Forschungsgemeischaft [SFB670, SFB829]
- European Commission (EC) [223404, 223151]
- Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC)
- European Research Council [ERC-2012-ADG_20120314]
- Humboldt research fellowship
- EMBO long-term fellowship
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The nuclear factor kappa B (NF-kappa B) signalling pathway exhibits both tumour-promoting and tumour-suppressing functions in different tissues and models of carcinogenesis. In particular in epidermal keratinocytes, NF-kappa B signalling was reported to exert primarily growth inhibitory and tumour-suppressing functions. Here, we show that mice with keratinocyte-restricted p65/RelA deficiency were resistant to 7, 12-dimethylbenz(a) anthracene (DMBA)-/12-O-tetra decanoylphorbol-13 acetate (TPA)-induced skin carcinogenesis. p65 deficiency sensitized epidermal keratinocytes to DNA damage-induced death in vivo and in vitro, suggesting that inhibition of p65-dependent prosurvival functions prevented tumour initiation by facilitating the elimination of cells carrying damaged DNA. In addition, lack of p65 strongly inhibited TPA-induced epidermal hyperplasia and skin inflammation by suppressing the expression of proinflammatory cytokines and chemokines by epidermal keratinocytes. Therefore, p65-dependent NF-kappa B signalling in keratinocytes promotes DMBA-/TPA-induced skin carcinogenesis by protecting keratinocytes from DNA damage-induced death and facilitating the establishment of a tumour-nurturing proinflammatory microenvironment.
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