title: miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling.
abstract: The emerging concept of generating cancer stem cells from epithelial-mesenchymal transition has attracted great interest; however, the factors and molecular mechanisms that govern this putative tumor-initiating process remain largely elusive. We report here that miR-200a not only regulates epithelial-mesenchymal transition but also stem-like transition in nasopharyngeal carcinoma cells. We first showed that stable knockdown of miR-200a promotes the transition of epithelium-like CNE-1 cells to the mesenchymal phenotype. More importantly, it also induced several stem cell-like traits, including CD133(+) side population, sphere formation capacity, in vivo tumorigenicity in nude mice, and stem cell marker expression. Consistently, stable overexpression of miR-200a switched mesenchyme-like C666-1 cells to the epithelial state, accompanied by a significant reduction of stem-like cell features. Furthermore, in vitro differentiation of the C666-1 tumor sphere resulted in diminished stem-like cell population and miR-200a induction. To investigate the molecular mechanism, we demonstrated that miR-200a controls epithelial-mesenchymal transition by targeting ZEB2, although it regulates the stem-like transition differentially and specifically by β-catenin signaling. Our findings reveal for the first time the function of miR-200a in shifting nasopharyngeal carcinoma cell states via a reversible process coined as epithelial-mesenchymal to stem-like transition through differential and specific mechanisms.
authors.affiliation: Brain Tumour Centre and Division of Neurosurgery, Department of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Hongping
authors.initials: H
authors.lastname: Xia
authors.forename: William K C
authors.initials: WK
authors.lastname: Cheung
authors.forename: Johnny
authors.initials: J
authors.lastname: Sze
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Songshan
authors.initials: S
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.forename: Wai Sang
authors.initials: WS
authors.lastname: Poon
authors.forename: Hsiang-fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Marie C
authors.initials: MC
authors.lastname: Lin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000074165:Zinc Finger E-box Binding Homeobox 2; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C492363:ZEB2 protein, human; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D051176:beta Catenin
references.citation: Mol Cancer Res. 2009 Mar;7(3):330-8
references.pmid: 19276181
references.citation: Cancer Res. 2007 Nov 15;67(22):10831-9
references.pmid: 18006828
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references.pmid: 12629218
references.citation: Cell Cycle. 2008 Mar 15;7(6):725-8
references.pmid: 18239456
references.citation: Cancer Res. 2007 Apr 1;67(7):3153-61
references.pmid: 17409422
references.citation: Nat Cell Biol. 2008 May;10(5):593-601
references.pmid: 18376396
references.citation: J Biol Chem. 2008 May 30;283(22):14910-4
references.pmid: 18411277
references.citation: Cancer Lett. 2010 Mar 28;289(2):151-60
references.pmid: 19748175
references.citation: Cell Cycle. 2008 Aug 15;7(16):2485-92
references.pmid: 18719380
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Cell. 2005 Jun 17;121(6):823-35
references.pmid: 15960971
references.citation: Mol Cell. 2001 Jun;7(6):1267-78
references.pmid: 11430829
references.citation: Nature. 2008 Apr 3;452(7187):650-3
references.pmid: 18385740
references.citation: Nature. 2007 Jan 4;445(7123):111-5
references.pmid: 17122771
references.citation: Trends Cell Biol. 2008 Aug;18(8):357-9
references.pmid: 18585040
references.citation: Mol Cell Biol. 2009 Nov;29(21):5923-40
references.pmid: 19703993
references.citation: Gastroenterology. 2007 Jun;132(7):2542-56
references.pmid: 17570225
references.citation: Nat Rev Cancer. 2006 Apr;6(4):259-69
references.pmid: 16557279
references.citation: Gynecol Oncol. 2009 Sep;114(3):457-64
references.pmid: 19501389
references.citation: Clin Cancer Res. 2009 Aug 15;15(16):5060-72
references.pmid: 19671845
references.citation: RNA Biol. 2008 Jul-Sep;5(3):115-9
references.pmid: 19182522
references.citation: Nature. 2004 Nov 18;432(7015):396-401
references.pmid: 15549107
references.citation: Cancer Res. 2008 Oct 1;68(19):7846-54
references.pmid: 18829540
references.citation: Cell Stem Cell. 2007 Nov;1(5):555-67
references.pmid: 18371393
references.citation: Biochem Biophys Res Commun. 2010 Jan 1;391(1):535-41
references.pmid: 19931509
references.citation: Oncogene. 2006 Oct 9;25(46):6188-96
references.pmid: 17028598
references.citation: Cancer. 2005 Nov 15;104(10):2092-8
references.pmid: 16206293
references.citation: EMBO Rep. 2008 Jun;9(6):582-9
references.pmid: 18483486
references.citation: Biochem Biophys Res Commun. 2009 Mar 6;380(2):205-10
references.pmid: 19135980
references.citation: Genes Dev. 2008 Apr 1;22(7):894-907
references.pmid: 18381893
references.citation: Nat Cell Biol. 2009 Dec;11(12):1487-95
references.pmid: 19935649
references.citation: J Natl Cancer Inst. 2007 Jun 20;99(12):936-48
references.pmid: 17565152
references.citation: J Biotechnol. 2007 Apr 30;129(2):352-65
references.pmid: 17275941
references.citation: PLoS One. 2008;3(10):e3544
references.pmid: 18958156
references.citation: Cancer Res. 2009 Sep 15;69(18):7135-9
references.pmid: 19738043
references.citation: Cancer Res. 2010 Feb 15;70(4):1441-8
references.pmid: 20124485
references.citation: Cell Cycle. 2008 Oct;7(20):3112-8
references.pmid: 18927505
references.citation: Head Neck. 2008 Jul;30(7):946-63
references.pmid: 18446839
references.citation: PLoS One. 2008 Aug 06;3(8):e2888
references.pmid: 18682804
references.citation: Stem Cells Dev. 2009 Oct;18(8):1127-34
references.pmid: 19409053
references.citation: Cell. 2009 Nov 25;139(5):871-90
references.pmid: 19945376
references.citation: Nat Rev Cancer. 2005 Sep;5(9):744-9
references.pmid: 16148886
references.citation: Nature. 1994 Feb 17;367(6464):645-8
references.pmid: 7509044
references.citation: Nature. 2001 Nov 1;414(6859):105-11
references.pmid: 11689955
references.citation: Cancer Res. 2007 Apr 15;67(8):3716-24
references.pmid: 17440084
references.citation: Stem Cells. 2009 Aug;27(8):1712-21
references.pmid: 19544444
references.citation: Nature. 2005 Apr 14;434(7035):843-50
references.pmid: 15829953
references.citation: Cancer Res. 2007 Feb 1;67(3):1030-7
references.pmid: 17283135
references.citation: Cancer Res. 2009 Apr 1;69(7):2887-95
references.pmid: 19276366
references.citation: Cancer Res. 2007 Nov 1;67(21):10538-45
references.pmid: 17974998
references.citation: Trends Mol Med. 2008 May;14(5):199-209
references.pmid: 18406208