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首页> 外文期刊>Cell cycle >miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions.
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miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions.

机译：miR-34和SNAIL形成双负反馈回路，以调节上皮-间质转化。

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摘要

Recently, the inhibition of epithelial-mesenchymal-transition (EMT) by p53 has been described as a new mode of tumor suppression which presumably prevents metastasis. Here we report that activation of p53 down-regulates the EMT-inducing transcription factor SNAIL via induction of the miR-34a/b/c genes. Suppression of miR-34a/b/c caused up-regulation of SNAIL and cells displayed EMT markers and related features, as enhanced migration and invasion. Ectopic miR-34a induced mesenchymal-epithelial-transition (MET) and down-regulation of SNAIL, which was mediated by a conserved miR-34a/b/c seed-matching sequence in the SNAIL 3'-UTR. miR-34a also down-regulated SLUG and ZEB1, as well as the stemness factors BMI1, CD44, CD133, OLFM4 and c-MYC. Conversely, the transcription factors SNAIL and ZEB1 bound to E-boxes in the miR-34a/b/c promoters, thereby repressing miR-34a and miR-34b/c expression. Since ectopic miR-34a prevented TGF-beta-induced EMT, the repression of miR-34 genes by SNAIL and related factors is part of the EMT program. In conclusion, the frequent inactivation of p53 and/or miR-34a/b/c found in cancer may shift the equilibrium of these reciprocal regulations towards the mesenchymal state and thereby lock cells in a metastatic state.
机译：最近，p53对上皮-间质转化（EMT）的抑制已被描述为一种新的肿瘤抑制模式，可以预防转移。在这里我们报告说，p53的激活通过miR-34a / b / c基因的诱导下调EMT诱导的转录因子SNAIL。 miR-34a / b / c的抑制导致SNAIL的上调，并且细胞显示出EMT标记和相关特征，并增强了迁移和侵袭。异位miR-34a诱导间质上皮转化（MET）和SNAIL的下调，这是由SNAIL 3'-UTR中保守的miR-34a / b / c种子匹配序列介导的。 miR-34a还下调了SLUG和ZEB1，以及干性因子BMI1，CD44，CD133，OLFM4和c-MYC。相反，转录因子SNAIL和ZEB1与miR-34a / b / c启动子中的E-box结合，从而抑制miR-34a和miR-34b / c的表达。由于异位miR-34a阻止了TGF-β诱导的EMT，因此SNAIL和相关因子对miR-34基因的抑制是EMT程序的一部分。总之，在癌症中频繁失活的p53和/或miR-34a / b / c可能会将这些相互调节的平衡朝着间充质状态转移，从而将细胞锁定在转移状态。

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