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

• Published in: Hepatology (Baltimore, Md.) Vol. 56; no. 3; pp. 1025 - 1033
• Main Authors: Callegari, Elisa, Elamin, Bahaeldin K., Giannone, Ferdinando, Milazzo, Maddalena, Altavilla, Giuseppe, Fornari, Francesca, Giacomelli, Luciano, D'Abundo, Lucilla, Ferracin, Manuela, Bassi, Cristian, Zagatti, Barbara, Corrà, Fabio, Miotto, Elena, Lupini, Laura, Bolondi, Luigi, Gramantieri, Laura, Croce, Carlo M., Sabbioni, Silvia, Negrini, Massimo
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2012; Wiley; Wolters Kluwer Health, Inc
• Subjects: Animals; Biological and medical sciences; Cyclin-dependent kinases; Gastroenterology. Liver. Pancreas. Abdomen; Hepatology; Kinases; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Transgenic; MicroRNAs; MicroRNAs - physiology; Rodents; Vertebrata; Mammalia; Mouse; Animal; Liver; Rodentia; Gastroenterology; Models; Tumorigenicity
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.25747

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. (HEPATOLOGY 2012;56:1025–1033)