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- Title
MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer.
- Authors
Asangani, I. A.; Rasheed, S. A. K.; Nikolova, D. A.; Leupold, J. H.; Colburn, N. H.; Post, S.; Allgayer, H.
- 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.Oncogene (2008) 27, 2128–2136; doi:10.1038/sj.onc.1210856; published online 29 October 2007
- Subjects
TUMOR suppressor genes; GENETIC regulation; COLON cancer; METASTASIS; CANCER invasiveness; MESSENGER RNA; GENE expression
- Publication
Oncogene, 2008, Vol 27, Issue 15, p2128
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210856