Document Detail


miR-200bc/429 cluster targets PLCgamma1 and differentially regulates proliferation and EGF-driven invasion than miR-200a/141 in breast cancer.
MedLine Citation:
PMID:  20514023     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The genes encoding microRNAs of the human miR-200 family map to fragile chromosomal regions and are frequently downregulated upon tumor progression. Although having been reported to regulate epithelial-to-mesenchymal transition and transforming growth factor-beta-driven cell invasion, the role of the miR-200 family in EGF-driven breast cancer cell invasion, viability, apoptosis and cell cycle progression is still unknown. In particular, there is no study comparing the roles of the two clusters of this miRNA family. In this study, we show for the first time that miR-200 family members differentially regulate EGF-driven invasion, viability, apoptosis and cell cycle progression of breast cancer cells. We showed that, all miR-200 family members regulate EGF-driven invasion, with the miR-200bc/429 cluster showing stronger effects than the miR-200a/141 cluster. Furthermore, expression of the miR-200a/141 cluster results in G1 arrest supported by increased p27/Kip1 and decreased cyclin dependent kinase 6 expression. In contrast, expression of the 200bc/429 cluster decreases G1 population and increases G2/M phase, in line with the observed reduction of p27/Kip1 and upregulation of the inhibitory phosphorylation of Cdc25C, respectively. To test the hypothesis that phenotypical differences observed between the two clusters are caused by differential targeting spectrums, we performed genome-wide microarray profiling in combination with gain-of-function studies. This identified phospholipase C gamma 1 (PLCG1), which was downregulated only by the miR-200bc/429 cluster, as a potential candidate contributing to these phenotypical differences. Luciferase reporter assays validated PLCG1 as a direct functional target of miR-200bc/429 cluster, but not of miR-200a/141 cluster. Finally, loss of PLCG1 in part mimicked the effect of miR-200bc/429 overexpression in viability, apoptosis and EGF-driven cell invasion of breast cancer cells. Our results suggest that the miR-200 family has a tumor-suppressor function by negatively regulating EGF-driven cell invasion, viability and cell cycle progression in breast cancer.
Authors:
S Uhlmann; J D Zhang; A Schwäger; H Mannsperger; Y Riazalhosseini; S Burmester; A Ward; U Korf; S Wiemann; O Sahin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-31
Journal Detail:
Title:  Oncogene     Volume:  29     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-29     Completed Date:  2010-08-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  4297-306     Citation Subset:  IM    
Affiliation:
Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis
Breast Neoplasms / pathology*
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cell Survival
Epidermal Growth Factor / physiology*
Female
Gene Expression Profiling
Humans
MicroRNAs / physiology*
Multigene Family
Neoplasm Invasiveness
Phospholipase C gamma / genetics*
Chemical
Reg. No./Substance:
0/MIRN141 microRNA, human; 0/MIRN200 microRNA, human; 0/MIRN429 microRNA, human; 0/MicroRNAs; 62229-50-9/Epidermal Growth Factor; EC 3.1.4.3/Phospholipase C gamma

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