Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial-mesenchymal transition of breast cancer cells
Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial-mesenchymal transition of breast cancer cells
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DOI：
10.1038/cdd.2010.103
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发表时间：
2011-01-01
影响因子：
12.4
通讯作者：
Xu, Z-D
中科院分区：
文献类型：
--
作者：
Li, Q-Q;Chen, Z-Q;Xu, Z-D
化疗药物诱导的上皮-间质转化（EMT）促进恶性肿瘤的进展，然而，药物诱导EMT的机制尚不清楚。在这项研究中，我们报道了miR-448是化疗后下调最多的microRNA。miR-448的抑制与体外和体内乳腺癌中的EMT诱导相关。通过使用染色质免疫沉淀-seq分析，我们证明了miR-448抑制通过直接靶向特殊的富含AT的序列结合蛋白-1（SATB 1）mRNA诱导EMT，导致双调蛋白水平升高，从而增加表皮生长因子受体（EGFR）介导的Twist 1表达以及核因子κ B（NF-κ B）激活。另一方面，我们还发现阿霉素激活的NF-κ B直接结合miR-448的启动子，抑制其转录，这表明NF-κ B和miR-448之间存在正反馈环。此外，所有接受环磷酰胺（CP）、表阿霉素加泰索帝/CP、表阿霉素加5-氟尿嘧啶化疗的患者均显示miR-448抑制、SATB 1、Twist 1表达增加和间充质表型获得。这些发现揭示了一个潜在的调节途径，其中NF-κ B B和miR-448之间的自动调节对于抑制化疗对miR-448的抑制是重要的，并且可能在化疗诱导的EMT的调节中起作用。在临床治疗过程中破坏NF-κ B-miR-448反馈环可能会改善人类乳腺癌的化疗反应，其中EMT是关键组分。Cell Death and Differentiation（2011）18，16-25; doi：10.1038/cdd.2010.103; 2010年8月27日在线发表
The epithelial-mesenchymal transition (EMT) induced by chemotherapeutic agents promotes malignant tumor progression; however, the mechanism underlying the drug-induced EMT remains unclear. In this study, we reported that miR-448 is the most downregulated microRNA following chemotherapy. Suppression of miR-448 correlated with EMT induction in breast cancer in vitro and in vivo. With the use of chromatin immunoprecipitation-seq analysis, we demonstrated that miR-448 suppression induces EMT by directly targeting special AT-rich sequence-binding protein-1 (SATB1) mRNA, leading to elevated levels of amphiregulin and thereby, increasing epidermal growth factor receptor (EGFR)-mediated Twist1 expression, as well as nuclear factor kappa B (NF-kappa B) activation. On the other hand, we also found that the adriamycin-activated NF-kappa B directly binds the promoter of miR-448 suppressing its transcription, suggesting a positive feedback loop between NF-kappa B and miR-448. Furthermore, all patients who received cyclophosphamide (CP), epirubicin plus taxotere/CP, epirubicin plus 5-fluorouracil chemotherapy showed miR-448 suppression, an increased SATB1, Twist1 expression and acquisition of mesenchymal phenotypes. These findings reveal an underlying regulatory pathway, in which the autoregulation between NF-kappa B and miR-448 is important for restrain miR-448 suppression upon chemotherapy and may have a role in the regulation of chemotherapy-induced EMT. Disruption of the NF-kappa B-miR-448 feedback loop during clinical treatment may improve the chemotherapy response of human breast cancers in which EMT is a critical component. Cell Death and Differentiation (2011) 18, 16-25; doi:10.1038/cdd.2010.103; published online 27 August 2010