Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial-mesenchymal transition of breast cancer cells.
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.
Li
Q-Q
QQ
Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Chen
Z-Q
ZQ
Cao
X-X
XX
Xu
J-D
JD
Xu
J-W
JW
Chen
Y-Y
YY
Wang
W-J
WJ
Chen
Q
Q
Tang
F
F
Liu
X-P
XP
Xu
Z-D
ZD
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
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
Cell. 2006 Mar 24;124(6):1169-81
16564011
Nature. 2005 Jun 9;435(7043):828-33
15944707
Cancer Res. 2004 Jun 1;64(11):3753-6
15172979
Cancer Res. 2008 Oct 1;68(19):7846-54
18829540
EMBO Rep. 2008 Jun;9(6):582-9
18483486
Cells Tissues Organs. 2007;185(1-3):157-61
17587821
Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8686-98
16361555
Int J Dev Biol. 2004;48(5-6):365-75
15349812
J Biol Chem. 2008 May 30;283(22):14910-4
18411277
J Cell Biol. 1992 Aug;118(3):741-51
1639855
Biochem Biophys Res Commun. 1999 Dec 9;266(1):167-73
10581184
J Biol Chem. 2001 Mar 9;276(10):7614-20
11108718
Cell. 2008 May 16;133(4):704-15
18485877
J Clin Invest. 2004 Aug;114(4):569-81
15314694
Cancer Res. 2008 Jan 15;68(2):516-20
18199547
Cancer Cell. 2006 Mar;9(3):189-98
16530703
Nature. 2008 Mar 13;452(7184):187-93
18337816
Int J Oncol. 2007 Aug;31(2):277-83
17611683
Cancer Res. 2006 May 1;66(9):4549-52
16651402
Cell. 2005 Mar 11;120(5):635-47
15766527
Cancer Res. 2005 Oct 15;65(20):9455-62
16230409
Exp Cell Res. 2006 Sep 10;312(15):2860-71
16828470
Biol Pharm Bull. 2006 May;29(5):903-6
16651716
Cancer Res. 2005 Dec 1;65(23):10801-9
16322226
Genes Dev. 2008 Apr 1;22(7):894-907
18381893
J Natl Cancer Inst. 1993 Apr 21;85(8):632-9
8096875
Development. 2005 Jul;132(14):3151-61
15983400
Nat Rev Cancer. 2002 Jun;2(6):442-54
12189386
Curr Opin Cell Biol. 2005 Oct;17(5):548-58
16098727
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
12434020
RNA. 2007 Aug;13(8):1172-8
17585049
Nat Cell Biol. 2008 May;10(5):593-601
18376396
Int J Cancer. 2006 Jan 15;118(2):290-301
16080193
Int J Cancer. 1997 Jul 29;72(3):512-7
9247297
Nature. 2008 Jul 3;454(7200):56-61
18548003
Cell. 2004 Jan 23;116(2):281-97
14744438
Cancer Cell. 2005 Sep;8(3):197-209
16169465
Mol Cancer Res. 2007 Aug;5(8):847-61
17670913
Cancer Res. 2006 Jun 15;66(12):6129-38
16778186
Clin Cancer Res. 2009 Apr 15;15(8):2657-65
19336515