Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential
Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential
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DOI：
10.1038/cdd.2013.148
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发表时间：
2014-02-01
影响因子：
12.4
通讯作者：
Berx, G.
中科院分区：
文献类型：
--
作者：
De Craene, B.;Denecker, G.;Berx, G.
EMT诱导转录因子Snail的表达在不同的人类癌症中增强。为了研究Snail在上皮癌进展过程中的体内作用，我们使用了皮肤特异性过表达Snail的小鼠模型。蜗牛转基因小鼠自发产生了不同组织学亚型的皮肤癌，例如基底细胞癌、鳞状细胞癌和皮脂腺癌。皮脂腺癌的发生与Blimp-1的直接和完全抑制密切相关，Blimp-1是皮脂细胞稳态的中心调节因子。角质形成细胞干细胞中的Snail表达显著促进其与激活的FoxM 1基因表达特征相关的增殖，从而产生更大的Mts 24标记的祖细胞库。此外，表达Snail的原代角质形成细胞显示出增加的存活率和对遗传毒性应激的强抗性。在皮肤特异性p53-null背景中的Snail表达导致自发性肿瘤的加速形成和增强的转移。我们的数据表明，在体内表达的Snail的结果在从头上皮癌的发生，允许增强生存，扩大癌症干细胞池与积累的DNA损伤，在终末分化和肿瘤起始细胞的增殖率增加的块。
Expression of the EMT-inducing transcription factor Snail is enhanced in different human cancers. To investigate the in vivo role of Snail during progression of epithelial cancer, we used a mouse model with skin-specific overexpression of Snail. Snail transgenic mice spontaneously developed distinct histological subtypes of skin cancer, such as basal cell carcinoma, squamous cell carcinoma and sebaceous gland carcinoma. Development of sebaceous gland carcinomas strongly correlated with the direct and complete repression of Blimp-1, a central regulator of sebocyte homeostasis. Snail expression in keratinocyte stem cells significantly promotes their proliferation associated with an activated FoxM1 gene expression signature, resulting in a larger pool of Mts24-marked progenitor cells. Furthermore, primary keratinocytes expressing Snail showed increased survival and strong resistance to genotoxic stress. Snail expression in a skin-specific p53-null background resulted in accelerated formation of spontaneous tumours and enhanced metastasis. Our data demonstrate that in vivo expression of Snail results in de novo epithelial carcinogenesis by allowing enhanced survival, expansion of the cancer stem cell pool with accumulated DNA damage, a block in terminal differentiation and increased proliferation rates of tumour-initiating cells.