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Oncogene ; 27(15): 2128-36, 2008 Apr 03.
Article in English | MEDLINE | ID: mdl-17968323

ABSTRACT

Tumor-suppressor Pdcd4 inhibits transformation and invasion and is downregulated in cancers. So far, it has not been studied as to whether miRNAs, suppressing target expression by binding to the 3'-UTR, regulate Pdcd4 or invasion. The present study was conducted to investigate the regulation of Pdcd4, and invasion/intra-vasation, by miRNAs. A bioinformatics search revealed a conserved target-site for miR-21 within the Pdcd4-3'-UTR at 228-249 nt. In 10 colorectal cell lines, an inverse correlation of miR-21 and Pdcd4-protein was observed. Transfection of Colo206f-cells with miR-21 significantly suppressed a luciferase-reporter containing the Pdcd4-3'-UTR, whereas transfection of RKO with anti-miR-21 increased activity of this construct. This was abolished when a construct mutated at the miR-21/nt228-249 target site was used instead. Anti-miR-21-transfected RKO cells showed an increase of Pdcd4-protein and reduced invasion. Moreover, these cells showed reduced intra-vasation and lung metastasis in a chicken-embryo-metastasis assay. In contrast, overexpression of miR-21 in Colo206f significantly reduced Pdcd4-protein amounts and increased invasion, while Pdcd4-mRNA was unaltered. Resected normal/tumor tissues of 22 colorectal cancer patients demonstrated an inverse correlation between miR-21 and Pdcd4-protein. This is the first study to show that Pdcd4 is negatively regulated by miR-21. Furthermore, it is the first report to demonstrate that miR-21 induces invasion/intravasation/metastasis.


Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/pathology , Apoptosis Regulatory Proteins/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , MicroRNAs/physiology , RNA Interference , RNA-Binding Proteins/genetics , Animals , Base Sequence , Caco-2 Cells , Chick Embryo , Down-Regulation , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , HCT116 Cells , HT29 Cells , Humans , Molecular Sequence Data , Neoplasm Invasiveness , Neoplasm Metastasis , Sequence Homology, Nucleic Acid , Tumor Cells, Cultured
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