Shukla Anjali, Ho Yan, Liu Xin, Ryscavage Andrew, Glick Adam B
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Mol Cancer Res. 2008 Mar;6(3):509-16. doi: 10.1158/1541-7786.MCR-07-0396.
Cripto-1 is an epidermal growth factor-Cripto/FRL1/Cryptic family member that plays a role in early embryogenesis as a coreceptor for Nodal and is overexpressed in human tumors. Here we report that in the two-stage mouse skin carcinogenesis model, Cripto-1 is highly up-regulated in tumor promoter-treated normal skin and in benign papillomas. Treatment of primary mouse keratinocytes with Cripto-1 stimulated proliferation and induced expression of keratin 8 but blocked induction of the normal epidermal differentiation marker keratin 1, changes that are hallmarks of tumor progression in squamous cancer. Chemical or genetic blockade of the transforming growth factor (TGF)-beta1 signaling pathway using the ALK5 kinase inhibitor SB431542 and dominant negative TGF-beta type II receptor, respectively, had similar effects on keratinocyte differentiation. Our results show that Cripto-1 could block TGF-beta1 receptor binding, phosphorylation of Smad2 and Smad3, TGF-beta-responsive luciferase reporter activity, and TGF-beta1-mediated senescence of keratinocytes. We suggest that inhibition of TGF-beta1 by Cripto-1 may play an important role in altering the differentiation state of keratinocytes and promoting outgrowth of squamous tumors in the mouse epidermis.
Cripto-1是表皮生长因子-Cripto/FRL1/Cryptic家族成员，在早期胚胎发育中作为Nodal的共受体发挥作用，且在人类肿瘤中过表达。在此我们报告，在两阶段小鼠皮肤癌发生模型中，Cripto-1在经肿瘤启动子处理的正常皮肤和良性乳头瘤中高度上调。用Cripto-1处理原代小鼠角质形成细胞可刺激增殖并诱导角蛋白8的表达，但会阻断正常表皮分化标志物角蛋白1的诱导，这些变化是鳞状细胞癌肿瘤进展的标志。分别使用ALK5激酶抑制剂SB431542和显性负性转化生长因子（TGF）-βII型受体对转化生长因子（TGF）-β1信号通路进行化学或基因阻断，对角质形成细胞分化有类似影响。我们的结果表明，Cripto-1可阻断TGF-β1受体结合、Smad2和Smad3的磷酸化、TGF-β反应性荧光素酶报告基因活性以及TGF-β1介导的角质形成细胞衰老。我们认为，Cripto-1对TGF-β1的抑制可能在改变角质形成细胞的分化状态和促进小鼠表皮鳞状肿瘤的生长中起重要作用。
