Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for snail, slug, and E47 factors in epithelial-mesenchymal transition
Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for snail, slug, and E47 factors in epithelial-mesenchymal transition
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DOI：
10.1158/0008-5472.can-06-0479
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Cano, Amparo
中科院分区：
文献类型：
--
作者：
Moreno-Bueno, Gerna;Cubillo, Eva;Cano, Amparo
转录因子Snail、Slug和bHLHE47最近被认为是E-钙粘素的直接抑制因子，当在上皮细胞中过表达时，可以诱导上皮-间充质转化(EMT)和侵袭。尽管这些因素在肿瘤进展和侵袭中的作用已被提出，但不同的抑制物在肿瘤发生过程中是否扮演不同或多余的角色尚未确定。为了进一步研究这一重要问题，我们利用基因芯片分析了表达不同阻遏基因(MDCK-Snail、MDCK-slug和MDCK-E47细胞)的MDCK上皮细胞与对照MDCK细胞的基因表达谱。共有243个克隆(228个基因和15个表达序列标签)在三个MDCK来源的细胞系和对照MDCK细胞之间差异表达。22个候选基因通过Northern印迹、Western印迹、免疫荧光和启动子分析在细胞系中以及在异种移植瘤中通过免疫组织化学进行了验证。基因聚类分析表明，在243个候选基因中，约有三分之一是表达Snail、Slug或E47因子的MDCK细胞共有的，而其余的基因只在一种或两种细胞类型中调控。差异表达基因包括与EMT(45个基因)、转录调控(18个基因)、细胞增殖和信号转导(54个基因)、细胞凋亡(12个基因)和血管生成(9个基因)相关的基因。这些结果表明，Snail、Slug和E47转录因子诱导共同和特定的遗传程序，支持这些因子在肿瘤进展和侵袭中的不同作用。
The transcription factors Snail, Slug, and bHLH E47 have been recently described as direct repressors of E-cadherin and inducers of epithelial-mesenchymal transition (EMT) and invasion when overexpressed in epithelial cells. Although a role of those factors in tumor progression and invasion has been proposed, whether the different repressors play distinct or redundant roles in the tumorigenic process has not been established. To further investigate this important issue, we have analyzed the gene expression profiling of Madin-Darby canine kidney (MDCK) epithelial cells expressing the different repressors (MDCK-Snail, MDCK-Slug, and MDCK-E47 cells) versus control MDCK cells by cDNA microarrays. A total of 243 clones (228 genes and 15 expressed sequence tags) were found to be differentially expressed between either of the three MDCK-derived cell lines and control MDCK cells. Twenty two of the candidate genes were validated by Northern blot, Western blot, immunofluorescence, and promoter analyses in cell lines and by immunohistochemistry in xenografted tumors. Gene clustering analysis indicated that about a third of the 243 candidate genes were common to MDCK cells expressing Snail, Slug, or E47 factors, whereas the rest of the genes were regulated in only one or two cell types. Differentially regulated genes include those related to EMT (45 genes), transcriptional regulation (18 genes), cell proliferation and signaling (54 genes), apoptosis (12 genes), and angiogenesis (9 genes). These results indicate that Snail, Slug, and E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion.