Mutant p53 induces EZH2 expression and promotes epithelial-mesenchymal transition by disrupting p68-Drosha complex assembly and attenuating miR-26a processing.
Mutant p53 induces EZH2 expression and promotes epithelial-mesenchymal transition by disrupting p68-Drosha complex assembly and attenuating miR-26a processing.
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突变体 p53 通过破坏 p68-Drosha 复合体组装和减弱 miR-26a 加工来诱导 EZH2 表达并促进上皮间质转化。
DOI：
10.18632/oncotarget.6350
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发表时间：
2015-12-29
期刊：
影响因子：
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通讯作者：
Wan XP
中科院分区：
文献类型：
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作者：
Jiang FZ;He YY;Wang HH;Zhang HL;Zhang J;Yan XF;Wang XJ;Che Q;Ke JQ;Chen Z;Tong H;Zhang YL;Wang FY;Li YR;Wan XP
肿瘤抑制因子p53和转录抑制因子增强子Zeste同源物2（EZH 2）均通过影响microRNA表达而参与上皮-间质转化（EMT）和肿瘤转移的调节。在这里，我们报告突变型p53（mutp 53）促进EMT子宫内膜癌（EC）通过破坏p68-Drosha复合物组装。mutp 53的过表达具有与野生型p53（WTP 53）相反的作用，其通过减少p53缺失的EC细胞中的pri-miR-26 a-1加工来抑制miR-26 a表达。miR-26 a在mutp 53 EC细胞中的再表达降低了细胞侵袭并促进了间充质-上皮转化（MET）。拯救miR-26 a表达还在体外和体内抑制EZH 2、N-钙粘蛋白、波形蛋白和Snail表达并诱导E-钙粘蛋白表达。此外，血清miR-26 a水平较高的患者具有更好的生存率。这些结果表明，p53功能获得性突变通过干扰Drosha和p68结合和pri-miR-26 a-1加工，导致miR-26 a表达减少和EZH 2过表达，加速EC肿瘤进展和转移。
The tumor suppressor p53 and the transcriptional repressor Enhancer of Zeste Homolog 2 (EZH2) have both been implicated in the regulation of epithelial-mesenchymal transition (EMT) and tumor metastasis via their impacts on microRNA expression. Here, we report that mutant p53 (mutp53) promotes EMT in endometrial carcinoma (EC) by disrupting p68-Drosha complex assembly. Overexpression of mutp53 has the opposite effect of wild-type p53 (WTp53), repressing miR-26a expression by reducing pri-miR-26a-1 processing in p53-null EC cells. Re-expression of miR-26a in mutp53 EC cells decreases cell invasion and promotes mesenchymal-epithelial transition (MET). Rescuing miR-26a expression also inhibits EZH2, N-cadherin, Vimentin, and Snail expression and induces E-cadherin expression both in vitro and in vivo. Moreover, patients with higher serum miR-26a levels have a better survival rate. These results suggest that p53 gain-of-function mutations accelerate EC tumor progression and metastasis by interfering with Drosha and p68 binding and pri-miR-26a-1 processing, resulting in reduced miR-26a expression and EZH2 overexpression.