MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways
MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways
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DOI：
10.1038/onc.2013.370
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发表时间：
2014-07-31
期刊：
影响因子：
8
通讯作者：
Khew-Goodall, Y.
中科院分区：
文献类型：
--
作者：
Li, X.;Roslan, S.;Khew-Goodall, Y.
microRNA-200（miR-200）家族通过抑制E-钙粘蛋白转录抑制因子ZEB 1和ZEB 2在调节上皮-间质转化和癌细胞侵袭中具有关键作用。最近的研究表明，miR-200家族可能在转移过程的不同阶段发挥作用，在同基因小鼠乳腺癌模型中具有增强转移的总体作用。我们在乳腺癌转移的异种移植原位模型中发现，miR-200 b/200 c/429成员的异位表达，而不是miR-141/200 a，功能组限制了肿瘤细胞的侵袭和转移。尽管ZEB 1-E-cadherin轴的调节，但在miR-200 b表达细胞中ZEB 1的恢复不能改变转移潜力，这表明其他靶点有助于这一过程。相反，我们发现miR-200 b抑制了几个肌动蛋白相关基因，其中ezrin-radixin-moesin家族成员moesin的敲除单独表现为miR-200 b对细胞侵袭的抑制。经验证，膜突蛋白被miR-200 b直接靶向，并且miR-200 b表达细胞中膜突蛋白的恢复足以减轻转移抑制。在乳腺癌细胞系和患者样本中，膜突蛋白的表达与miR-200的表达显著负相关，高水平的膜突蛋白与低无复发生存率相关。这些发现强调了miR-200在乳腺癌转移中的背景依赖性作用，并证明了与ZEB 1-E-cadherin轴不同的膜突蛋白依赖性途径的存在，miR-200可以通过该途径调节肿瘤细胞的可塑性和转移。
The microRNA-200 (miR-200) family has a critical role in regulating epithelial-mesenchymal transition and cancer cell invasion through inhibition of the E-cadherin transcriptional repressors ZEB1 and ZEB2. Recent studies have indicated that the miR-200 family may exert their effects at distinct stages in the metastatic process, with an overall effect of enhancing metastasis in a syngeneic mouse breast cancer model. We find in a xenograft orthotopic model of breast cancer metastasis that ectopic expression of members of the miR-200b/200c/429, but not the miR-141/200a, functional groups limits tumour cell invasion and metastasis. Despite modulation of the ZEB1-E-cadherin axis, restoration of ZEB1 in miR-200b-expressing cells was not able to alter metastatic potential suggesting that other targets contribute to this process. Instead, we found that miR-200b repressed several actin-associated genes, with the knockdown of the ezrin-radixin-moesin family member moesin alone phenocopying the repression of cell invasion by miR-200b. Moesin was verified to be directly targeted by miR-200b, and restoration of moesin in miR-200b-expressing cells was sufficient to alleviate metastatic repression. In breast cancer cell lines and patient samples, the expression of moesin significantly inversely correlated with miR-200 expression, and high levels of moesin were associated with poor relapse-free survival. These findings highlight the context-dependent effects of miR-200 in breast cancer metastasis and demonstrate the existence of a moesin-dependent pathway, distinct from the ZEB1-E-cadherin axis, through which miR-200 can regulate tumour cell plasticity and metastasis.