MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA.
Transforming growth factor beta (TGF-beta) signaling facilitates metastasis in advanced malignancy. While a number of protein-encoding genes are known to be involved in this process, information on the role of microRNAs (miRNAs) in TGF-beta-induced cell migration and invasion is still limited. By hybridizing a 515-miRNA oligonucleotide-based microarray library, a total of 28 miRNAs were found to be significantly deregulated in TGF-beta-treated normal murine mammary gland (NMuMG) epithelial cells but not Smad4 knockdown NMuMG cells. Among upregulated miRNAs, miR-155 was the most significantly elevated miRNA. TGF-beta induces miR-155 expression and promoter activity through Smad4. The knockdown of miR-155 suppressed TGF-beta-induced epithelial-mesenchymal transition (EMT) and tight junction dissolution, as well as cell migration and invasion. Further, the ectopic expression of miR-155 reduced RhoA protein and disrupted tight junction formation. Reintroducing RhoA cDNA without the 3' untranslated region largely reversed the phenotype induced by miR-155 and TGF-beta. In addition, elevated levels of miR-155 were frequently detected in invasive breast cancer tissues. These data suggest that miR-155 may play an important role in TGF-beta-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.
Kong
William
W
Departments of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., SRB3, Tampa, FL 33612, USA.
Yang
Hua
H
He
Lili
L
Zhao
Jian-jun
JJ
Coppola
Domenico
D
Dalton
William S
WS
Cheng
Jin Q
JQ
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D020742:rhoA GTP-Binding Protein
Nature. 2000 Feb 24;403(6772):901-6
10706289
Mol Biol Cell. 2000 Feb;11(2):555-65
10679014
Science. 2007 Apr 27;316(5824):604-8
17463289
Science. 2007 Apr 27;316(5824):608-11
17463290
J Biol Chem. 2005 Nov 25;280(47):38932-41
16174774
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
16461460
Bioinformatics. 2006 May 15;22(10):1177-82
16446276
Cell. 2005 Jan 14;120(1):15-20
15652477
Dev Cell. 2003 Aug;5(2):351-8
12919684
Science. 2005 Dec 16;310(5755):1817-21
16308420
Proc Natl Acad Sci U S A. 2006 May 2;103(18):7024-9
16641092
Oncogene. 2005 Aug 29;24(37):5764-74
16123809
J Cell Sci. 2007 Jun 1;120(Pt 11):1833-40
17515481
Nature. 2007 Oct 11;449(7163):682-8
17898713
Immunity. 2007 Dec;27(6):847-59
18055230
Nat Struct Mol Biol. 2007 Apr;14(4):287-94
17401373
J Virol. 2007 Dec;81(23):12836-45
17881434
Science. 2005 Mar 11;307(5715):1603-9
15761148
Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3627-32
15738415
Cancer Res. 2005 Aug 15;65(16):7065-70
16103053
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16170-5
17911264
Cancer Res. 2008 Jan 15;68(2):425-33
18199536
Cancer Res. 2006 Feb 15;66(4):2202-9
16489022
Trends Biochem Sci. 2005 Feb;30(2):106-14
15691656
Dev Cell. 2002 Sep;3(3):367-81
12361600
Cancer Cell. 2006 Mar;9(3):189-98
16530703
Cell. 2003 Feb 21;112(4):535-48
12600316
Nat Genet. 2007 Oct;39(10):1278-84
17893677
Mol Cell Biol. 2007 Mar;27(5):1859-67
17194750
Genes Dev. 2004 Mar 1;18(5):504-11
15014042
Nat Struct Mol Biol. 2006 Sep;13(9):849-51
16921378
EMBO Rep. 2008 Jun;9(6):582-9
18483486
Genes Dev. 2008 Apr 1;22(7):894-907
18381893
Nature. 2007 Dec 13;450(7172):1096-9
18075594
Science. 2003 Dec 5;302(5651):1775-9
14657501
J Biol Chem. 2008 Feb 1;283(5):2654-62
18048365
Nucleic Acids Res. 2003 Jan 1;31(1):374-8
12520026
Cancer Res. 2002 Jan 15;62(2):497-505
11809701
Cancer Res. 2006 Jun 15;66(12):6327-35
16778210
Cells Tissues Organs. 2007;185(1-3):157-61
17587821
PLoS Comput Biol. 2005 Jun;1(1):e13
16103902
Gene. 2001 Aug 22;274(1-2):157-67
11675008
Nature. 2004 Sep 16;431(7006):350-5
15372042
Nature. 2003 Sep 25;425(6956):415-9
14508493
Cell. 2003 Dec 26;115(7):787-98
14697198
Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1604-9
17242365
Nat Cell Biol. 2008 May;10(5):593-601
18376396
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8621-3
12861075
Genes Dev. 2004 Dec 15;18(24):3016-27
15574589
J Biol Chem. 2008 May 30;283(22):14910-4
18411277
Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13909-14
16172383
RNA. 2004 Dec;10(12):1957-66
15525708
Cell. 2005 Dec 16;123(6):1133-46
16337999
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D140-4
16381832
Oncogene. 2007 May 31;26(26):3769-76
17173072