Activation of Wnt/β-Catenin/Tcf signaling in mouse skin carcinogenesis
Activation of Wnt/β-Catenin/Tcf signaling in mouse skin carcinogenesis
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DOI：
10.1002/mc.20077
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发表时间：
2005-04-01
影响因子：
4.6
通讯作者：
Spiegelman, VS
中科院分区：
文献类型：
--
作者：
Bhatia, N;Spiegelman, VS
虽然Wnt/β-catenin/Tcf信号通路已被证明是许多恶性肿瘤包括结直肠癌、卵巢癌、前列腺癌和许多其他癌症的发展中的重要因素，但对其在非黑色素瘤皮肤癌中的作用知之甚少。在这里，我们报告的第一个证据表明，β-连环蛋白/Tcf信号通路是组成性激活的非黑素细胞的皮肤肿瘤诱导的两个阶段的化学致癌协议。小鼠皮肤肿瘤显示β-连环蛋白的细胞质和细胞核积聚，以及β-连环蛋白/Tcf靶基因（c-myc和c-jun）的上调。我们在肿瘤的不同部位发现了高水平的皮肤表达的Wnt蛋白（Wnt 3、4和10 b），这可能代表了小鼠皮肤癌变过程中β-连环蛋白/Tcf激活的关键上游事件。通过显性负性Tcf 4的异位表达抑制β-连环蛋白/Tcf信号传导导致鳞状细胞癌细胞生长的显著抑制。β-连环蛋白/Tcf信号转导的组成性激活在皮肤癌发生中的作用进行了讨论。(c)2005 Wiley-Liss，Inc.
Although Wnt/beta-catenin/Tcf signaling pathway has been shown to be an important factor in the development of many malignancies including colorectal, ovarian, prostate, and many other cancers, little is known about its role in non-melanoma skin cancers. Here, we report the first evidence that beta-catenin/Tcf signaling pathway is constitutively activated in non-melanocytic skin tumors induced by two stage chemical carcinogenesis protocol. Mouse skin tumors showed cytoplasmic and nuclear accumulation of P-catenin, and upregulation of beta-catenin/Tcf target genes (c-myc and c-jun). We found high levels of skin-expressed Wnt proteins (Wnt 3, 4, and 1 Ob) in different parts of the tumors, likely representing key upstream events in beta-catenin/Tcf activation during mouse skin carcinogenesis. Inhibition of beta-catenin/Tcf signaling by ectopic expression of dominant negative Tcf4 resulted in significant inhibition of growth in squamous cell carcinoma cells. A role of the constitutive activation of beta-catenin/Tcf signaling in skin carcinogenesis is discussed. (c) 2005 Wiley-Liss, Inc.