title: An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition.
abstract: Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-β (TGF-β) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-β signaling induced reversible DNA methylation of the miR-200 loci with corresponding changes in miR-200 levels. Collectively, these findings demonstrate the existence of an autocrine TGF-β/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-β and negative correlations between miR-200 and TGF-β and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-β/ZEB/miR-200 signaling network being active in breast cancers.
authors.affiliation: Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, SA 5000, Australia.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gregory
authors.forename: Cameron P
authors.initials: CP
authors.lastname: Bracken
authors.forename: Eric
authors.initials: E
authors.lastname: Smith
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bert
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Wright
authors.forename: Suraya
authors.initials: S
authors.lastname: Roslan
authors.forename: Melanie
authors.initials: M
authors.lastname: Morris
authors.forename: Leila
authors.initials: L
authors.lastname: Wyatt
authors.forename: Gelareh
authors.initials: G
authors.lastname: Farshid
authors.forename: Yat-Yuen
authors.initials: YY
authors.lastname: Lim
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.forename: M Frances
authors.initials: MF
authors.lastname: Shannon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Drew
authors.forename: Yeesim
authors.initials: Y
authors.lastname: Khew-Goodall
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D051340:Cofilin 2; D019175:DNA Methylation; D004285:Dogs; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D025461:Feedback, Physiological; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C495815:CFL2 protein, human; D051340:Cofilin 2; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1