Epidermal hyperplasia induced by Raf-MAPK signaling requires Stat3 activation

BackgroundRaf is one of the downstream effectors of Ras GTPases, and plays a key role in regulating cell proliferation and differentiation through the activation of MAPK. We have previously demonstrated that temporal induction of Raf in the epidermis of K14-Raf:ER transgenic mice results in epidermal hyperplasia resembling squamous cell carcinoma and psoriasis. It has been demonstrated that epidermal Stat3 activation is required for psoriasis development, since keratinocyte-specific Stat3 activation in a mouse model elicits a psoriasis-like phenotype, which is reversed by inhibition of Stat3 signaling.ObjectiveThe aim of this study was whether Stat3 signaling is involved in Raf-MAPK-dependent epidermal hyperplasia.MethodsK14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor ligand binding domain-Raf fusion gene is expressed under control of the keratin 14 promoter, were mated with epidermis-specific Stat3 null mice (K5-Cre.Stat3flox/flox). K5-Cre.Stat3flox/flox mice were used to define the impact of Stat3 deficiency on Raf-induced epidermal hyperplasia.ResultsOver-expression of Raf by 4OHT treatment in K14-Raf:ER;K5-Cre.Stat3flox/flox mice greatly attenuated the epidermal hyperplasia and dermal cell infiltrates compared with K14-Raf:ER;K5-Cre.Stat3flox/WT mice. Also, up-regulation of psoriasis-associated cytokine profiles, including VEGF, was inhibited in the skin from K14-Raf:ER;K5-Cre.Stat3flox/flox mice following 4OHT treatment.ConclusionThese results clearly indicate that Raf-MAPK-dependent psoriatic-like epidermal hyperplasia requires Stat3 signaling in keratinocytes.