title: Epidermal p65/NF-κB signalling is essential for skin carcinogenesis.
abstract: The nuclear factor kappa B (NF-κB) signalling pathway exhibits both tumour-promoting and tumour-suppressing functions in different tissues and models of carcinogenesis. In particular in epidermal keratinocytes, NF-κB 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-κB 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.
authors: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
authors: Chun
authors: C
authors: Kim
authors: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany pasparakis@uni-koeln.de.
authors: Manolis
authors: M
authors: Pasparakis
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017353:Gene Deletion; D015603:Keratinocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology*; D015398:Signal Transduction; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology*
chemical_list: D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D015127:9,10-Dimethyl-1,2-benzanthracene
keywords: NF‐κB signalling; apoptosis; inflammation; mouse models of cancer; skin carcinogenesis