Abstract
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.
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Abbreviations
- EMT:
-
epithelial–mesenchymal transition
- miRNA:
-
microRNA
- TSS:
-
transcription start site
- ChIP:
-
chromatin immunoprecipitation
- SATB1:
-
special AT-rich sequence-binding protein-1
- AR:
-
amphiregulin
- EGFR:
-
epidermal growth factor receptor
- NF-κB:
-
nuclear factor κB
- CK:
-
cytokeratin
- DM:
-
daunomycin
- CP:
-
cyclophosphamide
- 5-FU:
-
5-fluorouracil
- TAM:
-
tamoxifen
- CEF, cyclophosphamide:
-
epirubicin plus 5-fluorouracil
- CET, cyclophosphamide:
-
epirubicin plus taxotere
- CMF:
-
cyclophosphamide, methotrexate plus 5-fluorouracil
- MAPK:
-
mitogen-activated protein kinase
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Acknowledgements
This work was supported by grants from the National Nature Science Foundation of China (No. 81071813 and No. 30870972). We thank members of our laboratory for helpful discussions.
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Li, QQ., Chen, ZQ., Cao, XX. et al. Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial–mesenchymal transition of breast cancer cells. Cell Death Differ 18, 16–25 (2011). https://doi.org/10.1038/cdd.2010.103
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DOI: https://doi.org/10.1038/cdd.2010.103
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