Signal transducer and activator of transcription 3 (Stat3) is one of a family of cytoplasmic proteins that participate in normal cellular responses to cytokines and growth factors as transcription factors. Stat3 modulates various physiological functions including apoptosis, cell cycle regulation, and tumor angiogenesis through regulation of gene expression, and its constitutive activation is associated with a number of human epithelial cancers. In addition to the role of Stat3 in the development of skin tumors induced by chemical carcinogenesis regimen, recent studies from our group have shown that overexpression of Stat3 in keratinocytes reduced UVB-induced epidermal apoptosis, whereas Stat3-deficient keratinocytes were highly sensitive to UVB-induced apoptosis [Cancer Research 65:5720-5729, 2005]. Stat3 also was required for UVB-induced proliferation of follicular keratinocytes and epidermal thickening, implying its critical role in UV-induced skin cancer. Based on these results, transgenic mice whose keratinocytes express a constitutively active form of Stat3 (BK5.Stat3C) and wild-type mice were subjected to a UV skin carcinogenesis regimen to examine the potential role of Stat3 in UVB-induced skin carcinogenesis. BK5.Stat3C mice were more sensitive to UVB irradiation than wild-type controls as evidenced by differences in skin morphology after 10 weeks of UVB irradiation. In this regard, the skin of BK5.Stat3C mice showed an exaggerated response to UVB exposure as evidenced by severe inflammation and thickening of skin. These changes persisted with continued treatment. In addition, BK5.Stat3C mice show an exaggerated proliferative response to UVB treatment as assessed by BrdUrd incorporation. The results of this ongoing experiment will be reported in terms of tumor incidence and multiplicity. Based on all of our available data, we expect that BK5.Stat3C mice will develop more skin tumors in response to UVB exposure compared to wild-type mice.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]