The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2

MicroRNAs are small non-coding RNA molecules that can regulate gene expression by interacting with multiple mRNAs and inducing either translation suppression or degradation of mRNA. Recently, several miRNAs were identified as either promoters or suppressors of metastasis. However, it is unclear in w...

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Vydáno v:	The Journal of biological chemistry Ročník 283; číslo 22; s. 14910
Hlavní autoři:	Korpal, Manav, Lee, Esther S, Hu, Guohong, Kang, Yibin
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 30.05.2008
Témata:	Animals Cadherins - biosynthesis Cadherins - genetics Cell Movement - drug effects Cell Movement - genetics Epithelial Cells - metabolism Gene Expression Regulation, Neoplastic - drug effects Gene Expression Regulation, Neoplastic - genetics Genome, Human - genetics HeLa Cells Homeodomain Proteins - biosynthesis Homeodomain Proteins - genetics Humans Kruppel-Like Transcription Factors - biosynthesis Kruppel-Like Transcription Factors - genetics Mice MicroRNAs - biosynthesis MicroRNAs - genetics Multigene Family - genetics Neoplasm Metastasis Neoplasms - genetics Neoplasms - metabolism Repressor Proteins - biosynthesis Repressor Proteins - genetics Transcription Factors - biosynthesis Transcription Factors - genetics Transforming Growth Factor beta - pharmacology Zinc Finger E-box Binding Homeobox 2 Zinc Finger E-box-Binding Homeobox 1
ISSN:	0021-9258
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Popis
Shrnutí:	MicroRNAs are small non-coding RNA molecules that can regulate gene expression by interacting with multiple mRNAs and inducing either translation suppression or degradation of mRNA. Recently, several miRNAs were identified as either promoters or suppressors of metastasis. However, it is unclear in which step(s) of the multistep metastatic cascade these miRNAs play a defined functional role. To study the functional importance of miRNAs in epithelial-mesenchymal transition (EMT), a process thought to initiate metastasis by enhancing the motility of tumor cells, we used a well established in vitro EMT assay: transforming growth factor-beta-induced EMT in NMuMG murine mammary epithelial cells. We found that members of the miR-200 family, organized as two clusters in the genome, were repressed during EMT. Overexpression of each miRNA individually or as clusters in NMuMG cells hindered EMT by enhancing E-cadherin expression through direct targeting of ZEB1 and ZEB2, which encode transcriptional repressors of E-cadherin. In the 4TO7 mouse carcinoma cell line, which expresses low levels of endogenous E-cadherin and displays a mesenchymal phenotype, ectopic expression of the miR-200 family miRNAs significantly increased E-cadherin expression and altered cell morphology to an epithelial phenotype. Furthermore, ectopic expression of each miR-200 miRNA cluster significantly reduced the in vitro motility of 4TO7 cells in migration assays. These results suggested that loss of expression of the miR-200 family members may play a critical role in the repression of E-cadherin by ZEB1 and ZEB2 during EMT, thereby enhancing migration and invasion during cancer progression.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9258
DOI:	10.1074/jbc.C800074200