PMID- 19935649
OWN - NLM
STAT- MEDLINE
DCOM- 20091221
LR  - 20211203
IS  - 1476-4679 (Electronic)
IS  - 1465-7392 (Linking)
VI  - 11
IP  - 12
DP  - 2009 Dec
TI  - The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting 
      microRNAs.
PG  - 1487-95
LID - 10.1038/ncb1998 [doi]
AB  - 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.
FAU - Wellner, Ulrich
AU  - Wellner U
AD  - Department of Visceral Surgery, University of Freiburg, 79106 Freiburg, Germany.
FAU - Schubert, Jorg
AU  - Schubert J
FAU - Burk, Ulrike C
AU  - Burk UC
FAU - Schmalhofer, Otto
AU  - Schmalhofer O
FAU - Zhu, Feng
AU  - Zhu F
FAU - Sonntag, Annika
AU  - Sonntag A
FAU - Waldvogel, Bettina
AU  - Waldvogel B
FAU - Vannier, Corinne
AU  - Vannier C
FAU - Darling, Douglas
AU  - Darling D
FAU - zur Hausen, Axel
AU  - zur Hausen A
FAU - Brunton, Valerie G
AU  - Brunton VG
FAU - Morton, Jennifer
AU  - Morton J
FAU - Sansom, Owen
AU  - Sansom O
FAU - Schuler, Julia
AU  - Schuler J
FAU - Stemmler, Marc P
AU  - Stemmler MP
FAU - Herzberger, Christoph
AU  - Herzberger C
FAU - Hopt, Ulrich
AU  - Hopt U
FAU - Keck, Tobias
AU  - Keck T
FAU - Brabletz, Simone
AU  - Brabletz S
FAU - Brabletz, Thomas
AU  - Brabletz T
LA  - eng
GR  - C157/A9148/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091122
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (Homeodomain Proteins)
RN  - 0 (KLF4 protein, human)
RN  - 0 (Klf4 protein, mouse)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (MicroRNAs)
RN  - 0 (Transcription Factors)
RN  - 0 (ZEB1 protein, human)
RN  - 0 (ZEB1 protein, mouse)
RN  - 0 (Zinc Finger E-box-Binding Homeobox 1)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - *Cell Differentiation
MH  - Cell Line, Tumor
MH  - Epithelial Cells/cytology/metabolism
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Homeodomain Proteins/genetics/*metabolism
MH  - Humans
MH  - Kruppel-Like Factor 4
MH  - Kruppel-Like Transcription Factors/genetics/*metabolism
MH  - Male
MH  - Mesenchymal Stem Cells/cytology/metabolism
MH  - Mice
MH  - Mice, Nude
MH  - MicroRNAs/*genetics
MH  - Neoplasms/genetics/*metabolism/pathology
MH  - Sequence Alignment
MH  - Transcription Factors/*metabolism
MH  - Xenograft Model Antitumor Assays
MH  - Zinc Finger E-box-Binding Homeobox 1
EDAT- 2009/11/26 06:00
MHDA- 2009/12/22 06:00
CRDT- 2009/11/26 06:00
PHST- 2009/05/06 00:00 [received]
PHST- 2009/10/22 00:00 [accepted]
PHST- 2009/11/26 06:00 [entrez]
PHST- 2009/11/26 06:00 [pubmed]
PHST- 2009/12/22 06:00 [medline]
AID - ncb1998 [pii]
AID - 10.1038/ncb1998 [doi]
PST - ppublish
SO  - Nat Cell Biol. 2009 Dec;11(12):1487-95. doi: 10.1038/ncb1998. Epub 2009 Nov 22.