Abstract 5216: Impact of Stat3 deletion or activation on keratinocyte stem/progenitor cells

STATs play crucial roles in a wide variety of biological functions, including development, proliferation, differentiation and migration. Stat3 in particular plays a major role in cancer development. In the present study, we examined the impact of Stat3 deletion or activation on behavior of keratinocytes, including keratinocyte stem cells (KSCs) behavior in vivo. Initially, K5.Stat3C transgenic (Tg) mice which express a constitutively active/dimerized form of Stat3 called Stat3C via the bovine keratin 5 (K5) promoter were studied. The K5 promoter targets expression of Stat3C in the basal layer of the epidermis as well as in the bulge region KSCs. The number of CD34+ve/ alpha 6 integrin +ve cells was significantly reduced in Tg mice as compared to non-transgenic (NTg) littermates. There was a concomitant increase in the progenitor populations (Lgr-6, Lrig-1 and Sca-1) in the Tg mice vs. the stem cell population (CD34 and Keratin15). Activation of Stat3 in bulge region KSCs appeared to induce exit of these cells from this compartment. We also examined the effect of constitutive overexpression of Stat3 on the expression of classical differentiation markers (K1, K10, Loricrin and Involucrin) in the interfollicular epidermis as well as the hair follicle. Stat3C overexpression did not appear to alter expression of differentiation genes in the interfollicular epidermis. To investigate the mechanism underlying the increase in the progenitor population at the expense of bulge region KSCs we decided to examine if Stat3C overexpression was involved in inducing migration of the bulge region KSCs. Earlier work from our lab demonstrated that overexpression of Stat3C leads to upregulation of Twist in the epidermis, which suggests that Stat3 may be affecting migration in the BK5.Stat3C Tg mice. In addition, there was also increased β-catenin and decreased α6-integrin expression in the hair follicles of Tg mice, which may contribute to reduced adhesive interactions between the epithelial cells and the basement membrane also facilitating migration out of the niche. To further study the effect of Stat3 on differentiation of epidermal as well as stem cells we analyzed the epidermal keratinocytes in K5.Cre X Stat3 fl/fl mice where Stat3 is deleted in the basal epidermis and the outer root sheath of the hair follicle. There was an increase in the expression of epidermal differentiation markers in the Stat3 knockout mice. Also, there was an increase in the progenitor (Lgr-6, Lrig-1 and Sca-1) gene expression levels after TPA treatment in the Stat3 knockout mice. These data suggest that deletion of Stat3 in the epidermis and hair follicle induced differentiation in these cells. Overall, these data suggest that Stat3 plays an important role in differentiation as well as migration of keratinocytes and that these effects may play a role during epithelial carcinogenesis. Supported by NIH Grant CA76520. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5216. doi:1538-7445.AM2012-5216