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.

Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model / Callegari E.; Elamin B.K.; Giannone F.; Milazzo M.; Altavilla G.; Fornari F.; Giacomelli L.; D'Abundo L.; Ferracin M.; Bassi C.; Zagatti B.; Corrà F.; Miotto E.; Lupini L.; Bolondi L; Gramantieri L.; Croce C.M.; Sabbioni S.; Negrini M.. - In: HEPATOLOGY. - ISSN 0270-9139. - STAMPA. - 56:(2012), pp. 1025-1033. [10.1002/hep.25747]

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

FORNARI, FRANCESCA;FERRACIN, MANUELA;BOLONDI, LUIGI;
2012

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.
2012
Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model / Callegari E.; Elamin B.K.; Giannone F.; Milazzo M.; Altavilla G.; Fornari F.; Giacomelli L.; D'Abundo L.; Ferracin M.; Bassi C.; Zagatti B.; Corrà F.; Miotto E.; Lupini L.; Bolondi L; Gramantieri L.; Croce C.M.; Sabbioni S.; Negrini M.. - In: HEPATOLOGY. - ISSN 0270-9139. - STAMPA. - 56:(2012), pp. 1025-1033. [10.1002/hep.25747]
Callegari E.; Elamin B.K.; Giannone F.; Milazzo M.; Altavilla G.; Fornari F.; Giacomelli L.; D'Abundo L.; Ferracin M.; Bassi C.; Zagatti B.; Corrà F.; Miotto E.; Lupini L.; Bolondi L; Gramantieri L.; Croce C.M.; Sabbioni S.; Negrini M.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/119375
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