Abstract | UNLABELLED: MicroRNA-221 (miR-221) is one of the most frequently and consistently up-regulated microRNAs ( miRNAs) in human cancer. It has been hypothesized that miR-221 may act as a tumor promoter. To demonstrate this, we developed a transgenic (TG) mouse model that exhibits an inappropriate overexpression of miR-221 in the liver. Immunoblotting and immunostaining confirmed a concomitant down-regulation of miR-221 target proteins. This TG model is characterized by the emergence of spontaneous nodular liver lesions in approximately 50% of male mice and by a strong acceleration of tumor development in 100% of mice treated with diethylnitrosamine. Similarly to human hepatocellular carcinoma, tumors are characterized by a further increase in miR-221 expression and a concomitant inhibition of its target protein-coding genes (i.e., cyclin-dependent kinase inhibitor [Cdkn]1b/p27, Cdkn1c/p57, and B-cell lymphoma 2-modifying factor). To validate the tumor-promoting effect of miR-221, we showed that in vivo delivery of anti-miR-221 oligonucleotides leads to a significant reduction of the number and size of tumor nodules. CONCLUSIONS: This study not only establishes that miR-221 can promote liver tumorigenicity, but it also establishes a valuable animal model to perform preclinical investigations for the use of anti- miRNA approaches aimed at liver cancer therapy.
|
Authors | Elisa Callegari, Bahaeldin K Elamin, Ferdinando Giannone, Maddalena Milazzo, Giuseppe Altavilla, Francesca Fornari, Luciano Giacomelli, Lucilla D'Abundo, Manuela Ferracin, Cristian Bassi, Barbara Zagatti, Fabio Corrà, Elena Miotto, Laura Lupini, Luigi Bolondi, Laura Gramantieri, Carlo M Croce, Silvia Sabbioni, Massimo Negrini |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 56
Issue 3
Pg. 1025-33
(Sep 2012)
ISSN: 1527-3350 [Electronic] United States |
PMID | 22473819
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2012 American Association for the Study of Liver Diseases. |
Chemical References |
- MIRN221 microRNA, mouse
- MicroRNAs
|
Topics |
- Animals
- Liver Neoplasms
(genetics, pathology)
- Male
- Mice
- Mice, Transgenic
- MicroRNAs
(physiology)
|