title: The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs.
abstract: Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1-miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.
authors: Department of Visceral Surgery, University of Freiburg, 79106 Freiburg, Germany.
authors: Ulrich
authors: U
authors: Wellner
authors: Jörg
authors: J
authors: Schubert
authors: Ulrike C
authors: UC
authors: Burk
authors: Otto
authors: O
authors: Schmalhofer
authors: Feng
authors: F
authors: Zhu
authors: Annika
authors: A
authors: Sonntag
authors: Bettina
authors: B
authors: Waldvogel
authors: Corinne
authors: C
authors: Vannier
authors: Douglas
authors: D
authors: Darling
authors: Axel
authors: A
authors: zur Hausen
authors: Valerie G
authors: VG
authors: Brunton
authors: Jennifer
authors: J
authors: Morton
authors: Owen
authors: O
authors: Sansom
authors: Julia
authors: J
authors: Schüler
authors: Marc P
authors: MP
authors: Stemmler
authors: Christoph
authors: C
authors: Herzberger
authors: Ulrich
authors: U
authors: Hopt
authors: Tobias
authors: T
authors: Keck
authors: Simone
authors: S
authors: Brabletz
authors: Thomas
authors: T
authors: Brabletz
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016415:Sequence Alignment; D014157:Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D014157:Transcription Factors; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1