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.
Highlights
Cancer development occurs in a multistep process that can be subdivided into tumour initiation, promotion and progression (Hanahan & Weinberg, 2011)
To study the role of epidermal NF-jB signalling in skin carcinogenesis, we analysed the response of p65 gene in epidermal keratinocytes (p65EKO), heterozygous p65EHT and control p65 floxed (p65FL) mice to a well-established model of two-stage chemical carcinogenesis
Tumour initiation was elicited by a single topical application of 100 nmol DMBA, and tumour promotion was induced by twice weekly topical treatment with 5 nmol 12-O-tetra decanoylphorbol-13 acetate (TPA) for up to 21 weeks (Fig 1C)
Summary
Cancer development occurs in a multistep process that can be subdivided into tumour initiation, promotion and progression (Hanahan & Weinberg, 2011). Inflammation has emerged as a crucial mediator of tumour growth and progression. In this view, immune and stromal cells in the tumour microenvironment are believed to support the proliferation and survival of neoplastic cells and to promote vessel growth and tumour cell motility (Mantovani et al, 2008). Of various signalling cascades involved in inflammatory processes, the NF-jB pathway has drawn extensive attention as a key mediator providing a link between inflammation and tumorigenesis (Karin, 2006). In addition to its well-characterized function in inflammation and immunity, an increasing body of evidence supports that deregulation of NF-jB signalling both in tumour cells themselves and in stromal cells controls tumour growth
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