Sano Shigetoshi, Chan Keith Syson, DiGiovanni John
Department of Dermatology, Kochi Medical School, Kochi University, Okocho, Nankoku, Kochi 783-8505, Japan.
J Dermatol Sci. 2008 Apr;50(1):1-14. doi: 10.1016/j.jdermsci.2007.05.016. Epub 2007 Jul 2.
Signal transducer and activator of transcription 3 (Stat3) is a latent cytoplasmic protein that conveys signals to the nucleus upon stimulation with IL-6, EGF, and many other cytokines/growth factors, leading to transcriptional activation of the downstream genes. It has been well defined that Stat3 plays critical roles in biological activities including cell proliferation, migration, survival, and oncogenesis. The in vivo role for Stat3 in the skin was elucidated using keratinocyte-specific Stat3 gene knockout mice, referred to as Stat3-disrutped mice. It was shown that Stat3 activation contributed to skin wound healing, keratinocyte migration, hair follicle growth, and resistance to UV irradiation-induced apoptosis. Furthermore, in the two-stage chemical carcinogenesis protocol, Stat3-disrupted mice did not develop any skin tumors. In contrast, transgenic mice with a constitutive active form of Stat3 (K5.Stat3C mice) developed squamous cell carcinoma (SCC) with a shorter latency and in much greater number compared to control mice. These results suggested a role for Stat3 not only in early stages of skin carcinogenesis but also in driving malignant progression in vivo. Moreover, Stat3 was consistently activated in epidermal keratinocytes in human psoriatic lesions, which has been assumed to recapitulate a condition of persistent wound healing reaction. Accordingly, K5.Stat3C mice were found to be psoriasis-prone. Finally, it was demonstrated that an inhibition of Stat3 activation ameliorated these pathological conditions, i.e., skin carcinogenesis and psoriasis. Here we will review the dichotomous roles for Stat3 in maintaining skin homeostasis and in the development of skin diseases such as psoriasis and skin cancer.
信号转导与转录激活因子3（Stat3）是一种潜在的细胞质蛋白，在受到白细胞介素-6（IL-6）、表皮生长因子（EGF）和许多其他细胞因子/生长因子刺激后，会将信号传递至细胞核，从而导致下游基因的转录激活。Stat3在包括细胞增殖、迁移、存活和肿瘤发生在内的生物学活动中发挥关键作用，这一点已得到充分证实。利用角质形成细胞特异性Stat3基因敲除小鼠（即Stat3基因破坏小鼠）阐明了Stat3在皮肤中的体内作用。结果表明，Stat3的激活有助于皮肤伤口愈合、角质形成细胞迁移、毛囊生长以及抵抗紫外线照射诱导的细胞凋亡。此外，在两阶段化学致癌方案中，Stat3基因破坏小鼠未发生任何皮肤肿瘤。相反，与对照小鼠相比，具有组成型活性形式Stat3的转基因小鼠（K5.Stat3C小鼠）发生鳞状细胞癌（SCC）的潜伏期更短，数量更多。这些结果表明，Stat3不仅在皮肤癌发生的早期阶段起作用，而且在体内驱动恶性进展。此外，Stat3在人类银屑病皮损的表皮角质形成细胞中持续激活，这被认为重现了持续性伤口愈合反应的状态。因此，发现K5.Stat3C小鼠易患银屑病。最后，证明抑制Stat3激活可改善这些病理状况，即皮肤癌发生和银屑病。在此，我们将综述Stat3在维持皮肤稳态以及银屑病和皮肤癌等皮肤疾病发生发展中的双重作用。
