Role of Stat3 in Skin Carcinogenesis: Insights Gained from Relevant Mouse Models

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.

Tissue-specific conditional PKCε knockout mice: a model to precisely reveal PKCε functional role in initiation, promotion and progression of cancer

“…We have previously reported that PKCε levels in mouse epidermis dictates the susceptibility of mice to the development of cSCC elicited by UVR [28–35]. PKCε associates with Stat3 [15, 36]. Stat3 has two conserved amino acid residues (Tyr705 and Ser727) that are phosphorylated during Stat3 activation [15, 37].…”

Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

“…The signal transducer and activator of transcription 3 (STAT3) is a transcription factor activated in response to cytokines and growth factors, and plays critical role in various biological activities including cell proliferation, migration, and carcinogenesis (Macias et al , 2013). STAT3 is constitutively activated in cells transformed by the oncogenes v-Src and v-Abl, and in a variety of human cancers, including hematologic, pancreas, breast, head and neck, and prostate cancer (Bowman et al , 2000; Macias et al , 2013).…”

“…STAT3 is constitutively activated in cells transformed by the oncogenes v-Src and v-Abl, and in a variety of human cancers, including hematologic, pancreas, breast, head and neck, and prostate cancer (Bowman et al , 2000; Macias et al , 2013). Moreover, STAT3 is upregulated in both premalignant tumors (papillomas) and squamous cell carcinomas of mouse skin induced by topical treatment with DMBA + TPA (Chan et al , 2004).…”

The effect of resveratrol and its methylthio-derivatives on EGFR and Stat3 activation in human HaCaT and A431 cells

“…Stat3 activation is also associated with tumor survival and therapeutic resistance [6]. Many studies also have confirmed, the importance of Stat3 in skin carcinogenesis, skin cancer prevention, and treatment [4]. …”