Mutant p53 gain-of-function induces epithelial-mesenchymal transition through modulation of the miR-130b-ZEB1 axis.
Mutant p53 gain-of-function induces epithelial-mesenchymal transition through modulation of the miR-130b-ZEB1 axis.
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DOI：
10.1038/onc.2012.334
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发表时间：
2013-07-04
期刊：
影响因子：
8
通讯作者：
Sakuragi, N.
中科院分区：
文献类型：
--
作者：
Dong, P.;Karaayvaz, M.;Jia, N.;Kaneuchi, M.;Hamada, J.;Watari, H.;Sudo, S.;Ju, J.;Sakuragi, N.
肿瘤抑制基因p53通过调节微小RNA（miRNA）表达而参与调节上皮-间质转化（EMT）和肿瘤转移。在这里，我们报告突变型p53发挥致癌功能，并促进EMT子宫内膜癌（EC）直接结合到miR-130 b（ZEB 1的负调节）的启动子，并抑制其转录。我们将p53突变体转导到p53缺失的EC细胞中，通过miRNA微阵列分析miRNA表达，并将miR-130 b鉴定为突变体p53的潜在靶点。p53突变体的异位表达抑制了miR-130 b的表达，并触发了ZEB 1依赖的EMT和癌细胞侵袭。内源性p53突变的缺失增加了miR-130 b的表达，这导致ZEB 1表达减少和EMT表型减弱。此外，miR-130 b的再表达抑制突变型p53诱导的EMT和ZEB 1表达。重要的是，miR-130在EC组织中的表达显著降低，miR-130 b表达水平较高的患者存活时间更长。这些数据为p53功能获得性突变通过调节miR-130 b-ZEB 1轴加速肿瘤进展和转移的作用提供了新的理解。
The tumor suppressor gene p53 has been implicated in the regulation of epithelial–mesenchymal transition (EMT) and tumor metastasis by regulating microRNA (miRNA) expression. Here, we report that mutant p53 exerts oncogenic functions and promotes EMT in endometrial cancer (EC) by directly binding to the promoter of miR-130b (a negative regulator of ZEB1) and inhibiting its transcription. We transduced p53 mutants into p53-null EC cells, profiled the miRNA expression by miRNA microarray and identified miR-130b as a potential target of mutant p53. Ectopic expression of p53 mutants repressed the expression of miR-130b and triggered ZEB1-dependent EMT and cancer cell invasion. Loss of an endogenous p53 mutation increased the expression of miR-130b, which resulted in reduced ZEB1 expression and attenuation of the EMT phenotype. Furthermore, re-expression of miR-130b suppressed mutant p53-induced EMT and ZEB1 expression. Importantly, the expression of miR-130 was significantly reduced in EC tissues, and patients with higher expression levels of miR-130b survived longer. These data provide a novel understanding of the roles of p53 gain-of-function mutations in accelerating tumor progression and metastasis through modulation of the miR-130b–ZEB1 axis.
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