Genetic dissection of the miR-200-Zeb1 axis reveals its importance in tumor differentiation and invasion.
Genetic dissection of the miR-200-Zeb1 axis reveals its importance in tumor differentiation and invasion.
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DOI：
10.1038/s41467-018-07130-z
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发表时间：
2018-11-07
影响因子：
16.6
通讯作者：
Stoffel M
中科院分区：
文献类型：
--
作者：
Title AC;Hong SJ;Pires ND;Hasenöhrl L;Godbersen S;Stokar-Regenscheit N;Bartel DP;Stoffel M
上皮向间充质转化(EMT)是肿瘤进展和转移的重要机制。大量的体外和肿瘤图谱研究指出miR-200-ZEB1轴在调节这一过程中起关键作用，然而涉及其在生理背景下的调节的体内研究还很缺乏。在这里，我们表明，在Rip-Tag2胰岛素瘤小鼠模型中，miR-200消融诱导β细胞去分化，启动EMT表达程序，并促进肿瘤侵袭。引人注目的是，破坏内源ZEB1基因座的miR-200位点会导致类似的表型。在体外重新表达miR-200超家族成员表明，负责调控ZEB1和EMT的是miR-200C家族，而不是共同表达和密切相关的miR-141家族。因此，我们的结果表明，通过miR-200C扰乱ZEB1的体内调节足以推动EMT，从而突出了这一轴在肿瘤进展和侵袭中的重要性及其作为治疗靶点的潜力。在生理学背景下对上皮-间充质转化(EMT)的调节缺乏活体研究。本研究表明，在Rip-Tag2胰岛素瘤小鼠模型中，miR-200消融可诱导β细胞去分化、EMT和肿瘤侵袭，而miR-200C对ZEB1调节的干扰足以驱动EMT。
The epithelial-to-mesenchymal transition (EMT) is an important mechanism for cancer progression and metastasis. Numerous in vitro and tumor-profiling studies point to the miR-200–Zeb1 axis as crucial in regulating this process, yet in vivo studies involving its regulation within a physiological context are lacking. Here, we show that miR-200 ablation in the Rip-Tag2 insulinoma mouse model induces beta-cell dedifferentiation, initiates an EMT expression program, and promotes tumor invasion. Strikingly, disrupting the miR-200 sites of the endogenous Zeb1 locus causes a similar phenotype. Reexpressing members of the miR-200 superfamily in vitro reveals that the miR-200c family and not the co-expressed and closely related miR-141 family is responsible for regulation of Zeb1 and EMT. Our results thus show that disrupting the in vivo regulation of Zeb1 by miR-200c is sufficient to drive EMT, thus highlighting the importance of this axis in tumor progression and invasion and its potential as a therapeutic target. In vivo studies on the regulation of the epithelial-mesenchymal transition (EMT) within a physiological context are lacking. Here it is shown that miR-200 ablation in the Rip-Tag2 insulinoma mouse model induces beta-cell dedifferentiation, EMT and tumor invasion, and that disruption of Zeb1 regulation by miR-200c is sufficient to drive EMT.
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