Abstract
Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic protein that is activated in response to cytokines and growth factors and acts as a transcription factor. Stat3 plays critical roles in various biological activities including cell proliferation, migration, and survival. Studies using keratinocyte-specific Stat3-deficient mice have revealed that Stat3 plays an important role in skin homeostasis including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific Stat3-deficient mouse models has demonstrated that Stat3 is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of Stat3 (Stat3C) expressed in the basal layer of the epidermis revealed a novel role for Stat3 in skin tumor progression. Studies using similar Stat3-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis. This paper summarizes the use of these various mouse models for studying the role and underlying mechanisms for the function of Stat3 in skin carcinogenesis. Given its significant role throughout the skin carcinogenesis process, Stat3 is an attractive target for skin cancer prevention and treatment.
Highlights
Signal transducers and activators of transcription (Stats) are proteins that are activated by extracellular signaling proteins, such as growth factors, cytokines and various peptides [1]
We review the use of these mouse models and the insights gained regarding the role of Signal transducer and activator of transcription 3 (Stat3) in skin carcinogenesis
The status of Stat3 influenced the survival of cells containing ultraviolet B (UVB)-induced DNA photoproducts, including those cells located in the bulge region of the hair follicles through regulation of antiapoptotic genes such as Bcl-xL [23, 26]
Summary
Signal transducers and activators of transcription (Stats) are proteins that are activated by extracellular signaling proteins, such as growth factors, cytokines and various peptides [1]. The tumor progression stage occurs stochastically and leads to the conversion of skin papillomas to squamous cell carcinomas (SCCs) [11,12,13,14] In this model of skin carcinogenesis, Stat is activated very early in the epidermis following treatment with different classes of tumor promoters, including TPA, okadaic acid, and chrysarobin [15]. Loss-of-function studies have been complimented by a Stat mouse model expressing a constitutively activated Stat protein (Stat3C) under the control of the keratin 5 promoter (K5.Stat3C transgenic mice). Studies from this comprehensive set of skin-specific knockout and transgenic Stat mouse models have shown that Stat plays a major role in skin carcinogenesis. We review the use of these mouse models and the insights gained regarding the role of Stat in skin carcinogenesis
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