The transcription factors Snail and Slug activate the transforming growth factor-beta signaling pathway in breast cancer.
The transcription factors Snail and Slug activate the transforming growth factor-beta signaling pathway in breast cancer.
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转录因子蜗牛和SLUG激活了乳腺癌中转化的生长因子-BETA信号通路。
DOI：
10.1371/journal.pone.0026514
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wade PA
中科院分区：
文献类型：
--
作者：
Dhasarathy A;Phadke D;Mav D;Shah RR;Wade PA
转录抑制因子 Snail 和 Slug 位于多个信号通路的核心，这些信号通路被认为介导上皮间质转化或 EMT，这与肿瘤转移有关。 EMT 涉及从有组织的上皮细胞结构向间充质、侵袭性和迁移表型的改变。为了全面了解 Snail 和 Slug 表达的影响，我们使用 MCF-7 乳腺癌细胞系进行了微阵列实验，该细胞系不表达可检测水平的 Snail 或 Slug。 MCF-7 细胞被 Snail、Slug 或对照腺病毒感染，并对在不同时间点分离的 RNA 样本的所有转录本进行分析。我们的分析表明，Snail 和 Slug 调控许多共同的基因，但也有不同的基因目标集。基因集富集分析表明，Snail 和 Slug 将 MCF-7 细胞的转录组从管腔导向更复杂的模式，其中包括 Claudin-low 乳腺癌特征的许多特征。特别令人感兴趣的是，参与 TGF-β 信号通路的基因在 Snail 或 Slug 表达后上调，而负责分化形态的基因则下调。此外，我们注意到 Snail 或 Slug 表达后，转化生长因子 β 受体 II (TGFBR2) 基因启动子区域的组蛋白乙酰化增加。添加 Snail 或 Slug 后使用选择性小分子抑制剂抑制 TGF-β 信号通路，导致细胞迁移减少，但对 Snail 和 Slug 对细胞连接分子的抑制没有影响。我们提出 EMT 中嵌入了两个调节模块：一个涉及细胞连接分子的抑制，另一个涉及通过 TGF-β 和/或其他途径进行细胞迁移。
The transcriptional repressors Snail and Slug are situated at the core of several signaling pathways proposed to mediate epithelial to mesenchymal transition or EMT, which has been implicated in tumor metastasis. EMT involves an alteration from an organized, epithelial cell structure to a mesenchymal, invasive and migratory phenotype. In order to obtain a global view of the impact of Snail and Slug expression, we performed a microarray experiment using the MCF-7 breast cancer cell line, which does not express detectable levels of Snail or Slug. MCF-7 cells were infected with Snail, Slug or control adenovirus, and RNA samples isolated at various time points were analyzed across all transcripts. Our analyses indicated that Snail and Slug regulate many genes in common, but also have distinct sets of gene targets. Gene set enrichment analyses indicated that Snail and Slug directed the transcriptome of MCF-7 cells from a luminal towards a more complex pattern that includes many features of the claudin-low breast cancer signature. Of particular interest, genes involved in the TGF-beta signaling pathway are upregulated, while genes responsible for a differentiated morphology are downregulated following Snail or Slug expression. Further we noticed increased histone acetylation at the promoter region of the transforming growth factor beta-receptor II (TGFBR2) gene following Snail or Slug expression. Inhibition of the TGF-beta signaling pathway using selective small-molecule inhibitors following Snail or Slug addition resulted in decreased cell migration with no impact on the repression of cell junction molecules by Snail and Slug. We propose that there are two regulatory modules embedded within EMT: one that involves repression of cell junction molecules, and the other involving cell migration via TGF-beta and/or other pathways.
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影响因子：
2.7
作者：
Fan C;Prat A;Parker JS;Liu Y;Carey LA;Troester MA;Perou CM
通讯作者：
Perou CM
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
影响因子：
6.5
作者：
Frazier, K;Williams, S;Grotendorst, GR
通讯作者：
Grotendorst, GR
影响因子：
5.3
作者：
Kajita, M;McClinic, KN;Wade, PA
通讯作者：
Wade, PA
影响因子：
4
作者：
Ikenouchi, J;Matsuda, M;Tsukita, S
通讯作者：
Tsukita, S