Constitutive activation and targeted disruption of signal transducer and activator of transcription 3 (Stat3) in mouse epidermis reveal its critical role in UVB-induced skin carcinogenesis.
In this study, the potential role of Stat3 in UVB-induced skin carcinogenesis was examined using skin-specific gain and loss of function transgenic mice, that is, K5.Stat3C and K5Cre.Stat3(fl/fl) mice, respectively. The epidermis of Stat3-deficient mice was highly sensitive to UVB-induced apoptosis, whereas the epidermis of K5.Stat3C mice was more resistant to UVB-induced apoptosis. In particular, the status of Stat3 influenced the survival of ultraviolet-photoproduct cells, including those located in the hair follicles. K5.Stat3C mice exhibited significantly increased epidermal proliferation and hyperplasia in response to UVB irradiation, whereas Stat3-deficient mice showed reduced epidermal proliferation and hyperplasia. Expression of target genes regulated by Stat3, such as cyclin D1 and Bcl-x(L), was increased in epidermis of both control and UVB-irradiated K5.Stat3C mice, and downregulated in epidermis of both control and UVB-irradiated K5Cre.Stat3(fl/fl) mice. Following UVB irradiation, the formation of skin tumors in K5.Stat3C mice was accelerated and both the incidence and multiplicity of skin tumors were significantly greater than wild-type controls. In contrast, Stat3-deficient mice were resistant to UVB skin carcinogenesis. These results show that Stat3 plays an important role in the development of UVB-induced skin tumors through its effects on both survival and proliferation of keratinocytes during carcinogenesis.
Kim
D J
DJ
Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA.
Angel
J M
JM
Sano
S
S
DiGiovanni
J
J
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology; D014466:Ultraviolet Rays; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; C503688:CCNE2 protein, human; C530105:Ccnd1 protein, mouse; D016213:Cyclins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051020:bcl-X Protein; D019938:Cyclin D1; C045073:Cre recombinase; D019426:Integrases