Regulation of the MicroRNA 200b (miRNA-200b) by Transcriptional Regulators PEA3 and ELK-1 Protein Affects Expression of Pin1 Protein to Control Anoikis*
Regulation of the MicroRNA 200b (miRNA-200b) by Transcriptional Regulators PEA3 and ELK-1 Protein Affects Expression of Pin1 Protein to Control Anoikis*
复制标题
DOI：
10.1074/jbc.m113.478016
复制
发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Xusen Zhang;Bailin Zhang;Ji-dong Gao;Xiang Wang;Zhihua Liu
中科院分区：
文献类型：
--
作者：
Xusen Zhang;Bailin Zhang;Ji-dong Gao;Xiang Wang;Zhihua Liu
背景：miRNA-200 b在失巢凋亡调控中的作用尚不清楚。结果：miRNA-200 b通过靶向Pin 1调控失巢凋亡，其表达受PEA 3和ELK-1调控。结论：Pin 1是miRNA-200 b的功能靶基因。意义：这些发现表征了miRNA-200 b的自我调节及其在失巢凋亡调控中的作用。MicroRNA（miRNA）200通过直接靶向E-cadherin的转录抑制因子ZEB 1/ZEB 2来调节E-cadherin。E-cadherin表达的降低导致癌细胞失去与细胞外基质的相互作用并从原发性肿瘤中脱离。通常，细胞在失去与细胞外基质的相互作用后将经历失巢凋亡。因此，癌细胞必须具有在转移过程中抵抗失巢凋亡的能力。我们发现miRNA-200 b通过直接靶向Pin 1 mRNA的3′ UTR并在翻译水平上调节Pin 1的表达来调节失巢凋亡。我们发现，miRNA-200 b的下调促进癌细胞在转移过程中的存活，并且这些细胞的无家可归状态导致MCF-7细胞系中miRNA-200 b的表达降低。我们还发现，在乳腺癌淋巴结转移过程中，miRNA-200 b表达下调，与Pin 1表达呈显著负相关。ETS（E-26）家族的两个成员（PEA 3和ELK-1）调节miRNA-200 b的表达。PEA 3促进miRNA-200 b的表达，ELK-1是miRNA-200 b的转录抑制因子。此外，miRNA-200 b通过Pin 1-pERK通路调节PEA 3和ELK-1的活性，并形成自我调节的反馈环。本研究描述了miRNA-200 b在失巢凋亡调控中的作用，并证明了其自身表达在转移过程中的调节。
Background: The role of miRNA-200b in the regulation of anoikis is not well understood. Results: miRNA-200b controls anoikis by targeting Pin1, and its expression is regulated by PEA3 and ELK-1. Conclusion: Pin1 acts as a functional target gene of miRNA-200b. Significance: These findings characterize the self-regulation of miRNA-200b and its role in the regulation of anoikis. MicroRNA (miRNA) 200s regulate E-cadherin by directly targeting ZEB1/ZEB2, which are transcriptional repressors of E-cadherin. Decreased expression of E-cadherin results in cancer cells losing interaction with the extracellular matrix and detaching from the primary tumor. Normally, cells will undergo anoikis after losing interaction with the extracellular matrix. Cancer cells must, therefore, possess the ability to resist anoikis during the process of metastasis. Here we show that miRNA-200b regulates anoikis by directly targeting the 3′ UTR of Pin1 mRNA and regulating Pin1 expression at the translational level. We found that down-regulation of miRNA-200b promotes cancer cells survival during metastasis, and the homeless state of these cells resulted in decreased expression of miRNA-200b in the MCF-7 cell line. We also found that expression of miRNA-200b is down-regulated in human breast cancer during lymph node metastasis, which has a significant negative correlation with Pin1 expression. Two members of the ETS (E-26) family (PEA3 and ELK-1) regulate the expression of miRNA-200b. PEA3 promotes the expression of miRNA-200b, and ELK-1 is a transcriptional repressor of miRNA-200b. In addition, miRNA-200b regulates the activity of PEA3 and ELK-1 via the Pin1-pERK pathway and forms self-regulated feedback loops. This study characterizes the role of miRNA-200b in the regulation of anoikis and demonstrates the regulation of its own expression in the process of metastasis.