miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells.
miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells.
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DOI：
10.1002/stem.101
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发表时间：
2009-08
期刊：
影响因子：
5.2
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Kong, Dejuan;Li, Yiwei;Wang, Zhiwei;Banerjee, Sanjeev;Ahmad, Aamir;Kim, Hyeong-Reh Choi;Sarkar, Fazlul H.
关键词：
MicroRNAs与肿瘤进展有关。最近的研究表明，miR-200家族通过靶向锌指E-box结合同源盒1 （ZEB1）和ZEB2调控上皮-间充质转化（EMT）。来自我们实验室和其他实验室的新证据表明，EMT的过程可以由多种生长因子触发，如转化生长因子-β (TGF-β)和血小板衍生生长因子- d （PDGF-D）。此外，我们最近报道了前列腺癌细胞（PC3 PDGF-D细胞）中PDGF-D的过表达导致EMT表型的获得，该模型为研究PDGF-D信号传导与EMT之间的分子相互作用提供了机会。本研究首次报道了miR-200家族在PC3 PDGF-D细胞以及暴露于纯化活性PDGF-D蛋白的PC3细胞中显著下调，导致ZEB1、ZEB2和snail2表达上调。有趣的是，在PC3 PDGF-D细胞中重新表达miR-200b导致EMT表型逆转，这与ZEB1、ZEB2和snail2表达下调有关，这些结果与上皮标记物基因表达增加一致。此外，用miR-200b转染PC3 PDGF-D细胞可以抑制细胞迁移和侵袭，同时抑制细胞对培养表面的粘附和细胞脱离。从这些结果中，我们得出结论，PDGF-D诱导PC3细胞获得EMT表型的部分原因是miR-200的抑制，任何可以上调miR-200的新策略都将成为治疗侵袭性前列腺癌的有希望的方法。
MicroRNAs have been implicated in tumor progression. Recent studies have shown that miR-200 family regulates Epithelial-Mesenchymal Transition (EMT) by targeting zinc-finger E-box binding homeobox 1 (ZEB1) and ZEB2. Emerging evidence from our laboratory and others suggest that the processes of EMT can be triggered by various growth factors such as Transforming Growth Factor-beta (TGF-β) and Platelet-Derived Growth Factor-D (PDGF-D). Moreover, we have recently reported that over-expression of PDGF-D in prostate cancer cells (PC3 PDGF-D cells) leads to the acquisition of EMT phenotype, and this model offers an opportunity for investigating the molecular interplay between PDGF-D signaling and EMT. Here we report, for the first time, significant down-regulation of miR-200 family in PC3 PDGF-D cells as well as in PC3 cells exposed to purified active PDGF-D protein, resulting in the up-regulation of ZEB1, ZEB2 and snail2 expression. Interestingly, re-expression of miR-200b in PC3 PDGF-D cells led to the reversal of EMT phenotype, which was associated with the down-regulation of ZEB1, ZEB2 and snail2 expression and these results were consistent with increased gene expressions of epithelial markers. Moreover, transfection of PC3 PDGF-D cells with miR-200b inhibited cell migration and invasion with concomitant repression of cell adhesion to culture surface and cell detachment. From these results, we conclude that PDGF-D induced acquisition of EMT phenotype of PC3 cells is in part due to repression of miR-200 and that any novel strategies by which miR-200 could be up-regulated would become a promising approach for the treatment of invasive prostate cancer.
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