CPEB1 mediates epithelial-to-mesenchyme transition and breast cancer metastasis.
CPEB1 mediates epithelial-to-mesenchyme transition and breast cancer metastasis.
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DOI：
10.1038/onc.2015.350
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发表时间：
2016-06-02
期刊：
影响因子：
8
通讯作者：
Richter JD
中科院分区：
文献类型：
--
作者：
Nagaoka K;Fujii K;Zhang H;Usuda K;Watanabe G;Ivshina M;Richter JD
在小鼠乳腺上皮细胞中，CPEB 1介导ZO-1 mRNA的顶端定位，ZO-1 mRNA编码一个关键的紧密连接组分。在缺乏CPEB 1的小鼠和CPEB已耗尽的培养细胞中，随机分布的ZO-1 mRNA导致细胞极性丧失。我们已经研究了这种极性的减少是否会导致上皮细胞向间充质细胞（EMT）的转化以及可能增加的转移潜能。在这里，我们表明，CPEB 1耗尽的乳腺上皮细胞以与EMT一致的方式改变其基因表达谱，并且也变得能动，当细胞用TGF-β（EMT的增强剂）处理时，这一点变得特别强大。CPEB 1耗尽的乳腺细胞在注射到小鼠脂肪垫中后转移到肺，而异位表达的CPEB 1防止转移。令人惊讶的是，CPEB 1缺失导致一些EMT/转移相关mRNA具有较短的poly（A）尾，而其他mRNA具有较长的poly（A）尾。基质金属蛋白酶9（MMP 9）mRNA，编码一种转移促进因子，在CPEB减少时经历聚（A）延长和增强的翻译。此外，在转移性越来越强的人乳腺癌细胞中，CPEB 1减少，而MMP 9变得更加丰富。这些数据表明，至少部分地，CPEB 1调节MMP 9 mRNA表达介导的乳腺癌细胞的转移。
In mouse mammary epithelial cells, CPEB1 mediates the apical localization of ZO-1 mRNA, which encodes a critical tight junction component. In mice lacking CPEB1 and in cultured cells from which CPEB has been depleted, randomly distributed ZO-1 mRNA leads to the loss of cell polarity. We have investigated whether this diminution of polarity results in an epithelial-to-mesenchyme (EMT) transition and possible increased metastatic potential. Here, we show that CPEB1-depleted mammary epithelial cells alter their gene expression profile in a manner consistent with an EMT and also become motile, which are made particularly robust when cells are treated with TGF-β, an enhancer of EMT. CPEB1-depleted mammary cells become metastatic to the lung following injection into mouse fat pads while ectopically-expressed CPEB1 prevents metastasis. Surprisingly, CPEB1 depletion causes some EMT/metastasis-related mRNAs to have shorter poly(A) tails while other mRNAs to have longer poly(A) tails. Matrix metalloproteinase 9 (MMP9) mRNA, which encodes a metastasis-promoting factor, undergoes poly(A) lengthening and enhanced translation upon CPEB reduction. Moreover, in human breast cancer cells that become progressively more metastatic, CPEB1 is reduced while MMP9 becomes more abundant. These data suggest that at least in part, CPEB1 regulation of MMP9 mRNA expression mediates metastasis of breast cancer cells.