Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model.

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)