The mir-200 family and mir-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1
The mir-200 family and mir-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1
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DOI：
10.1038/ncb1722
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发表时间：
2008-05-01
影响因子：
21.3
通讯作者：
Goodall, Gregory J.
中科院分区：
文献类型：
--
作者：
Gregory, Philip A.;Bert, Andrew G.;Goodall, Gregory J.
上皮间质转化（EMT）促进胚胎发育过程中的组织重塑，并被视为肿瘤转移的重要早期步骤。我们发现microRNA-200家族的所有五个成员（miR-200 a，miR-200 b，miR-200 c，miR- 141和miR- 429）和miR- 205在经历EMT的细胞中显著下调，以响应转化生长因子（TGF）-β或蛋白酪氨酸磷酸酶Pez的异位表达。单独的miR- 200家族的强制表达足以防止TGF-β诱导的EMT。这些microRNA共同调节E-钙粘蛋白转录抑制因子ZEB 1（也称为delta EF 1）和SIP 1（也称为ZEB 2）的表达，这些因子先前与EMT和肿瘤转移有关。对microRNA的抑制足以在需要上调ZEB 1和/或SIP 1的过程中诱导EMT。相反，这些microRNA在间充质细胞中的异位表达启动了间充质向上皮转化（MET）。与它们在调节EMT中的作用一致，发现这些microRNA的表达在具有间充质表型的侵袭性乳腺癌细胞系中丢失。miR- 200家族的表达也在缺乏E-钙粘蛋白的化生性乳腺癌标本中丢失。这些数据表明，microRNA的下调可能是肿瘤进展中的重要步骤。
Epithelial to mesenchymal transition (EMT) facilitates tissue remodelling during embryonic development and is viewed as an essential early step in tumour metastasis. We found that all five members of the microRNA-200 family (miR- 200a, miR- 200b, miR- 200c, miR- 141 and miR- 429) and miR- 205 were markedly downregulated in cells that had undergone EMT in response to transforming growth factor (TGF)-beta or to ectopic expression of the protein tyrosine phosphatase Pez. Enforced expression of the miR- 200 family alone was sufficient to prevent TGF-beta-induced EMT. Together, these microRNAs cooperatively regulate expression of the E-cadherin transcriptional repressors ZEB1 ( also known as delta EF1) and SIP1 ( also known as ZEB2), factors previously implicated in EMT and tumour metastasis. Inhibition of the microRNAs was sufficient to induce EMT in a process requiring upregulation of ZEB1 and/or SIP1. Conversely, ectopic expression of these microRNAs in mesenchymal cells initiated mesenchymal to epithelial transition ( MET). Consistent with their role in regulating EMT, expression of these microRNAs was found to be lost in invasive breast cancer cell lines with mesenchymal phenotype. Expression of the miR- 200 family was also lost in regions of metaplastic breast cancer specimens lacking E-cadherin. These data suggest that downregulation of the microRNAs may be an important step in tumour progression.