CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression
CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression
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DOI：
10.1172/jci44540
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发表时间：
2011-03-01
影响因子：
15.9
通讯作者：
Cheng, Chonghui
中科院分区：
文献类型：
--
作者：
Brown, Rhonda L.;Reinke, Lauren M.;Cheng, Chonghui
上皮-间质转化（EMT）是一个严格调控的过程，对胚胎发生至关重要，但在癌症转移和复发期间异常激活。在这里，我们表明，CD 44选择性剪接的开关是EMT所必需的。使用体外和体内系统，我们已经证明了在EMT过程中CD 44表达从变体亚型（CD 44 v）到标准亚型（CD 44 s）的转变。这种向CD 44 s的同种型转换对于细胞进行EMT是必不可少的，并且是小鼠中显示EMT特征的乳腺肿瘤形成所必需的。从机制上讲，剪接因子上皮剪接调节蛋白1（ESRP 1）控制CD 44亚型转换，并且对于调节EMT表型至关重要。此外，CD 44 s亚型激活Akt信号传导，为驱动EMT的关键途径提供了机制联系。最后，CD 44 s表达在高级别的人乳腺肿瘤中上调，并且与这些肿瘤中的间充质标记物N-钙粘蛋白的水平相关。总之，我们的数据表明，调节CD 44选择性剪接因果关系有助于EMT和乳腺癌的进展。
Epithelial-mesenchymal transition (EMT) is a tightly regulated process that is critical for embryogenesis but is abnormally activated during cancer metastasis and recurrence. Here we show that a switch in CD44 alternative splicing is required for EMT. Using both in vitro and in vivo systems, we have demonstrated a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) during EMT. This isoform switch to CD44s was essential for cells to undergo EMT and was required for the formation of breast tumors that display EMT characteristics in mice. Mechanistically, the splicing factor epithelial splicing regulatory protein 1 (ESRP1) controlled the CD44 isoforrn switch and was critical for regulating the EMT phenotype. Additionally, the CD44s isoform activated Akt signaling, providing a mechanistic link to a key pathway that drives EMT. Finally, CD44s expression was upregulated in high-grade human breast tumors and was correlated with the level of the mesenchymal marker N-caciherin in these tumors. Together, our data suggest that regulation of CD44 alternative splicing causally contributes to EMT and breast cancer progression.