title: Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial-mesenchymal transition of breast cancer cells.
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.
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Q-Q
authors.initials: QQ
authors.lastname: Li
authors.forename: Z-Q
authors.initials: ZQ
authors.lastname: Chen
authors.forename: X-X
authors.initials: XX
authors.lastname: Cao
authors.forename: J-D
authors.initials: JD
authors.lastname: Xu
authors.forename: J-W
authors.initials: JW
authors.lastname: Xu
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Chen
authors.forename: W-J
authors.initials: WJ
authors.lastname: Wang
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Tang
authors.forename: X-P
authors.initials: XP
authors.lastname: Liu
authors.forename: Z-D
authors.initials: ZD
authors.lastname: Xu
mesh_terms: D066258:Amphiregulin; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000627:therapeutic use; D066255:EGF Family of Proteins; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000903:Antibiotics, Antineoplastic; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C557400:MIRN448 microRNA, human; D036961:Matrix Attachment Region Binding Proteins; D035683:MicroRNAs; D016328:NF-kappa B; D009687:Nuclear Proteins; C076189:SATB1 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D004317:Doxorubicin; D066246:ErbB Receptors
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