title: Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model.
abstract: 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.affiliation: Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Callegari
authors.forename: Bahaeldin K
authors.initials: BK
authors.lastname: Elamin
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Giannone
authors.forename: Maddalena
authors.initials: M
authors.lastname: Milazzo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Altavilla
authors.forename: Francesca
authors.initials: F
authors.lastname: Fornari
authors.forename: Luciano
authors.initials: L
authors.lastname: Giacomelli
authors.forename: Lucilla
authors.initials: L
authors.lastname: D'Abundo
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferracin
authors.forename: Cristian
authors.initials: C
authors.lastname: Bassi
authors.forename: Barbara
authors.initials: B
authors.lastname: Zagatti
authors.forename: Fabio
authors.initials: F
authors.lastname: Corrà
authors.forename: Elena
authors.initials: E
authors.lastname: Miotto
authors.forename: Laura
authors.initials: L
authors.lastname: Lupini
authors.forename: Luigi
authors.initials: L
authors.lastname: Bolondi
authors.forename: Laura
authors.initials: L
authors.lastname: Gramantieri
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Silvia
authors.initials: S
authors.lastname: Sabbioni
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
mesh_terms: D000818:Animals; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*
chemical_list: C546122:MIRN221 microRNA, mouse; D035683:MicroRNAs