Identifying inhibitors of epithelial-mesenchymal transition by connectivity map-based systems approach.
Identifying inhibitors of epithelial-mesenchymal transition by connectivity map-based systems approach.
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DOI：
10.1097/jto.0b013e31822adfb0
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Keshamouni VG
中科院分区：
文献类型：
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作者：
Reka AK;Kuick R;Kurapati H;Standiford TJ;Omenn GS;Keshamouni VG
上皮细胞通过上皮间质转化（EMT）获得间质表型被认为是肿瘤转移多步骤过程中的早期事件。因此，抑制EMT可能是预防转移的合理策略。利用 TGF-β 诱导的 EMT 细胞培养模型的全局基因表达谱，我们鉴定了潜在的 EMT 抑制剂。我们使用了一个公开数据库（www.broad.mit.edu/cmap），该数据库包含从多种不同细胞系获得的基因表达谱，以响应各种药物，并使用连接图（C-Map）（一种模式匹配工具）得出与 EMT 基因表达谱的负相关性。对已鉴定化合物的实验验证表明，雷帕霉素与 17-AAG（已知的 TGF-β 途径调节剂）一样，都是 TGF-β 信号传导的新型抑制剂。这两种化合物完全阻断 EMT 以及相关的迁移和侵袭表型。另一种鉴定出的化合物 LY294002 表现出对间充质标记物、细胞迁移和侵袭的选择性抑制，而不影响 E-钙粘蛋白表达或 Smad 磷酸化的丧失。总的来说，我们的数据表明雷帕霉素是一种新型 TGF-β 信号传导调节剂，与 17-AAG 和 LY294002 一起可用作抑制 EMT 的治疗剂。此外，该分析还证明了系统方法在识别复杂生物过程的新型调节剂方面的潜力。
Acquisition of mesenchymal phenotype by epithelial cells by means of epithelial mesenchymal transition (EMT) is considered as an early event in the multi-step process of tumor metastasis. Therefore, inhibition of EMT might be a rational strategy to prevent metastasis. Utilizing the global gene expression profile from a cell culture model of TGF-β-induced EMT, we identified potential EMT inhibitors. We used a publicly available database (www.broad.mit.edu/cmap) comprising gene expression profiles obtained from multiple different cell lines in response to various drugs to derive negative correlations to EMT gene expression profile using Connectivity Map (C-Map), a pattern matching tool. Experimental validation of the identified compounds showed rapamycin as a novel inhibitor of TGF-β signaling along with 17-AAG, a known modulator of TGF-β pathway. Both of these compounds completely blocked EMT and the associated migratory and invasive phenotype. The other identified compound, LY294002, demonstrated a selective inhibition of mesenchymal markers, cell migration and invasion, without affecting the loss of E-cadherin expression or Smad phosphorylation. Collectively, our data reveals that rapamycin is a novel modulator of TGF-β signaling, and along with 17-AAG and LY294002, could be used as therapeutic agent for inhibiting EMT. Also, this analysis demonstrates the potential of a systems approach in identifying novel modulators of a complex biological process.