Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis
Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis
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DOI：
10.1038/sj.onc.1210726
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发表时间：
2008-02-14
期刊：
影响因子：
8
通讯作者：
DiGiovanni, J.
中科院分区：
文献类型：
--
作者：
Chan, K. S.;Sano, S.;DiGiovanni, J.
最近，我们的实验室证明Stat 3是化学诱导的皮肤肿瘤从头发展所必需的。我们使用小鼠进一步研究了Stat 3在上皮癌发生中的作用，其中Stat 3的组成型活性/二聚化形式（Stat 3C）的表达靶向表皮的增殖区室（称为K5.Stat3C转基因小鼠）。角质细胞来自K5。Stat 3C小鼠在暴露于7，12-二甲基-苯并[ a]蒽（DMBA）后表现出存活率增加，并且在暴露于12-O-十四酰基佛波醇-13-乙酸酯（TPA）后表现出增殖增强。在以DMBA为肿瘤引发剂、TPA为促进剂的两阶段化学致癌实验中，K5.与非转基因同窝小鼠相比，Stat 3C小鼠发生皮肤肿瘤的潜伏期更短，数量更多。值得注意的是，100%的皮肤肿瘤发生在K5。Stat 3C转基因小鼠绕过癌前阶段，最初被诊断为原位癌，迅速发展为鳞状细胞癌（SCC）。这些肿瘤高度血管化，分化差，侵袭性和损失的表达K10，聚丝蛋白和E-钙粘蛋白观察到20周。最后，Stat 3C在乳头状瘤细胞系中的过表达导致在生长因子存在和不存在的情况下通过基质胶增强细胞迁移和增强侵袭。除了其在上皮癌变早期阶段的关键作用外，目前的研究揭示了Stat 3在体内驱动皮肤肿瘤恶性进展中的新作用。
Recently, our laboratory demonstrated that Stat3 is required for the de novo development of chemically-induced skin tumors. We have further investigated the role of Stat3 in epithelial carcinogenesis using mice in which the expression of a constitutively active/ dimerized form of Stat3 ( Stat3C) is targeted to the proliferative compartment of epidermis ( referred to as K5.Stat3C transgenic mice). Keratinocytes from K5. Stat3C mice showed increased survival following exposure to 7,12-dimethyl-benz[ a] anthracene ( DMBA) and enhanced proliferation following exposure to 12-O-tetradecanoylphorbol-13-acetate ( TPA). In two-stage chemical carcinogenesis experiments using DMBA as the tumor initiator and TPA as the promoter, K5. Stat3C mice developed skin tumors witha shorter latency and in much greater number compared to non-transgenic littermates. Remarkably, 100% of the skin tumors that developed in K5. Stat3C transgenic mice bypassed the premalignant stage and were initially diagnosed as carcinoma in situ which rapidly progressed to squamous cell carcinoma ( SCC). These tumors were highly vascularized, poorly differentiated and invasive and loss of expression of K10, filaggrin and E-cadherin was observed by 20 weeks. Finally, overexpression of Stat3C in a papilloma cell line led to enhanced cell migration and enhanced invasion through Matrigel in both the absence and presence of growth factors. In addition to its critical role in early stages of epithelial carcinogenesis, the current study reveals a novel role for Stat3 in driving malignant progression of skin tumors in vivo.