All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis
All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis
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DOI：
10.1158/1940-6207.capr-09-0041
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发表时间：
2009-10
影响因子：
3.3
通讯作者：
Zanobia A Syed;S. Cheepala;Jennifer N Gill;J. Stein;C. Nathan;J. DiGiovanni;V. Batra;P. Adegboyega;H. Kleiner;J. Clifford
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文献类型：
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作者：
Zanobia A Syed;S. Cheepala;Jennifer N Gill;J. Stein;C. Nathan;J. DiGiovanni;V. Batra;P. Adegboyega;H. Kleiner;J. Clifford
皮肤鳞状细胞癌（SCC）是临床上最具侵袭性的非黑色素瘤皮肤癌。我们已经确定了全反式维甲酸（ATRA），一种天然存在的化学预防性类维生素A，对信号转导和转录激活因子3（Stat 3）信号在皮肤SCC的发展过程中的影响。Stat 3是一种在细胞增殖和存活中起关键作用的转录因子，并且在几种恶性细胞类型中具有组成性活性。我们以前已经表明，Stat 3是皮肤SCC的启动，促进和进展所必需的。ATRA在两阶段小鼠皮肤癌发生模型中是一种高效的肿瘤形成抑制剂，我们已经证明这种作用与B-Raf/Mek/Erk信号通路的抑制相关。在这项研究中，我们已经确定了整个过程中的两个阶段的协议，在ATRA的存在和不存在的Stat 3磷酸化的模式。我们使用了SENCAR小鼠和K5.Stat3C转基因小鼠，它们在皮肤中表达Stat 3C蛋白，这是Stat 3的组成型活性形式。使用蛋白质印迹和免疫组织化学染色与磷酸特异性抗体，我们表明，ATRA的共同管理抑制12-O-十四烷酰佛波醇-13-乙酸酯诱导的磷酸化的Stat 3在这两个模型中，但只能抑制肿瘤形成的SENCAR小鼠。令人惊讶的是，ATRA实际上增强了12-O-十四酰基佛波醇-13-乙酸酯治疗的K5.Stat3C小鼠的肿瘤形成。我们假设ATRA阻断肿瘤形成，至少部分是通过靶向Stat 3上游的事件，如B-Raf/Mek/Erk通路，并且在K5.Stat3C小鼠中，其中Stat 3活性是组成性的，它不能抑制肿瘤形成。
Squamous cell carcinoma (SCC) of the skin is the most clinically aggressive form of nonmelanoma skin cancer. We have determined the effects of all-trans retinoic acid (ATRA), a naturally occurring chemopreventive retinoid, on signal transducer and activator of transcription 3 (Stat3) signaling during the development of skin SCC. Stat3 is a transcription factor that plays a critical role in cell proliferation and survival, and it is constitutively active in several malignant cell types. We have previously shown that Stat3 is required for the initiation, promotion, and progression of skin SCC. ATRA is a highly efficient suppressor of tumor formation in the two-stage mouse skin carcinogenesis model and we have shown that this effect correlates with the suppression of the B-Raf/Mek/Erk signaling pathway. In this study, we have determined the pattern of Stat3 phosphorylation throughout the course of the two-stage protocol, both in the presence and absence of ATRA. We have used both SENCAR mice and K5.Stat3C transgenic mice, which express the Stat3C protein, a constitutively active form of Stat3, in the skin. Using Western blotting and immunohistochemical staining with phosphospecific antibodies, we show that coadministration of ATRA suppressed the 12-O-tetradecanoylphorbol-13-acetate–induced phosphorylation of Stat3 in both models, but was only able to suppress tumor formation in the SENCAR mice. Surprisingly, ATRA actually enhanced tumor formation in 12-O-tetradecanoylphorbol-13-acetate–treated K5.Stat3C mice. We hypothesize that ATRA blocks tumor formation, at least in part, by targeting events upstream of Stat3, such as the B-Raf/Mek/Erk pathway, and that in the K5.Stat3C mice, in which Stat3 activity is constitutive, it cannot suppress tumor formation.