miR-200a Regulates SIRT1 Expression and Epithelial to Mesenchymal Transition (EMT)-like Transformation in Mammary Epithelial Cells
miR-200a Regulates SIRT1 Expression and Epithelial to Mesenchymal Transition (EMT)-like Transformation in Mammary Epithelial Cells
复制标题
DOI：
10.1074/jbc.m111.229401
复制
发表时间：
2011-07-22
影响因子：
4.8
通讯作者：
Zhou, Qun
中科院分区：
文献类型：
--
作者：
Eades, Gabriel;Yao, Yuan;Zhou, Qun
有证据表明，microrna （mirna）在组织特异性分化和发育的调控中起着关键作用。与健康组织相比，表达谱揭示了肿瘤中广泛的miRNA失调，这标志着这些程序的中断。miR-200家族已被确定为上皮表型的关键调节因子，因此，在乳腺癌中深入参与上皮到间充质转化（EMT）过程。然而，miR-200家族对正常乳腺上皮细胞转化的影响尚未得到充分表征。通过检查tgf - β驱动的正常乳腺上皮转化模型，我们证明了III类组蛋白去乙酰化酶沉默信息调节因子1 (SIRT1)，一种被提出的乳腺癌致癌基因，在emt样转化中过度表达，miR-200a的表观遗传沉默至少在一定程度上导致了SIRT1的过度表达。我们通过miR-200a靶向SIRT1 3'-UTR，建立了SIRT1转录本受miR-200a调控。我们还观察到SIRT1和miR-200a参与了负反馈调节回路。miR-200a的恢复或SIRT1的敲低阻止了正常乳腺上皮细胞的转化，这可以通过减少非锚定生长和减少细胞迁移来证明。最后，我们在乳腺癌患者样本中观察到SIRT1过表达与miR-200a降低相关。这些观察结果进一步证明了miR-200家族在乳腺上皮中具有重要的肿瘤抑制作用，此外还发现了一种新的调控机制，可能有助于SIRT1在乳腺癌中的上调。
Evidence supports a critical role for microRNAs (miRNAs) in regulation of tissue-specific differentiation and development. Signifying a disruption of these programs, expression profiling has revealed extensive miRNA dysregulation in tumors compared with healthy tissue. The miR-200 family has been established as a key regulator of epithelial phenotype and, as such, is deeply involved in epithelial to mesenchymal transition (EMT) processes in breast cancer. However, the effects of the miR-200 family on transformation of normal mammary epithelial cells have yet to be fully characterized. By examining a TGF-beta driven model of transformation of normal mammary epithelium, we demonstrate that the class III histone deacetylase silent information regulator 1 (SIRT1), a proposed oncogene in breast cancer, is overexpressed upon EMT-like transformation and that epigenetic silencing of miR-200a contributes at least in part to the overexpression of SIRT1. We have established the SIRT1 transcript as subject to regulation by miR-200a, through miR-200a targeting of SIRT1 3'-UTR. We also observed SIRT1 and miR-200a participation in a negative feedback regulatory loop. Restoration of miR-200a or the knockdown of SIRT1 prevented transformation of normal mammary epithelial cells evidenced by decreased anchorage-independent growth and decreased cell migration. Finally, we observed SIRT1 overexpression in association with decreased miR-200a in breast cancer patient samples. These observations provide further evidence for a critical tumor suppressive role of the miR-200 family in breast epithelium in addition to identifying a novel regulatory mechanism, which may contribute to SIRT1 up-regulation in breast cancer.