Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Cell Death Differ. 2011 Jan;18(1):16-25. doi: 10.1038/cdd.2010.103. Epub 2010 Aug 27.
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 κB (NF-κB) activation. On the other hand, we also found that the adriamycin-activated NF-κB directly binds the promoter of miR-448 suppressing its transcription, suggesting a positive feedback loop between NF-κB 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-κB 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-κB-miR-448 feedback loop during clinical treatment may improve the chemotherapy response of human breast cancers in which EMT is a critical component.
上皮-间充质转化（EMT）被化疗药物诱导，促进恶性肿瘤进展；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 是化疗后下调最明显的 microRNA。miR-448 的抑制与体外和体内乳腺癌的 EMT 诱导相关。通过染色质免疫沉淀-seq 分析，我们证明 miR-448 的抑制通过直接靶向特殊富含 AT 的序列结合蛋白-1（SATB1）mRNA 诱导 EMT，导致 Amphiregulin 水平升高，从而增加表皮生长因子受体（EGFR）介导的 Twist1 表达以及核因子 κB（NF-κB）的激活。另一方面，我们还发现阿霉素激活的 NF-κB 直接结合 miR-448 的启动子，抑制其转录，提示 NF-κB 和 miR-448 之间存在正反馈环。此外，所有接受环磷酰胺（CP）、表柔比星加紫杉醇/CP、表柔比星加 5-氟尿嘧啶化疗的患者均表现出 miR-448 抑制、SATB1、Twist1 表达增加和获得间充质表型。这些发现揭示了一个潜在的调控途径，其中 NF-κB 和 miR-448 之间的自动调节对于抑制化疗后 miR-448 的抑制很重要，并且可能在调节化疗诱导的 EMT 中发挥作用。在临床治疗过程中破坏 NF-κB-miR-448 反馈回路可能会改善 EMT 是关键组成部分的人类乳腺癌的化疗反应。
