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. image p65‐dependent NF ‐κB signalling in keratinocytes promotes DMBA ‐/ TPA ‐induced skin carcinogenesis by protecting them from DNA damage‐induced death. Keratinocyte‐specific knockout of p65/RelA prevents DMBA ‐/ TPA ‐induced skin tumorigenesis in mice. p65 deficiency sensitizes keratinocytes to DNA damage‐induced apoptosis p65 deficiency inhibits TPA ‐induced expression of inflammatory cytokines and chemokines by keratinocytes Keratinocyte‐specific p65 deficiency prevents TPA ‐induced inflammation and epidermal hyperplasia in vivo .