miR-221 is one of the most frequently and consistently up-regulated microRNAs in human cancer. It has been hypothesized that miR-221 may act as a tumor promoter. To fully prove it, we developed a transgenic mouse model that exhibits an inappropriate over-expression of miR-221 in the liver. Immunoblotting and immunostaining confirmed a concomitant down-regulation of miR-221 target proteins. This transgenic model is characterized by the emergence of spontaneous nodular liver lesions in about 50% of male mice and by a strong acceleration of tumor development in 100% of mice treated with diethylnitrosamine. Similarly to human HCC, tumors are characterized by a further increase in miR-221 expression and a concomitant inhibition of its target protein coding genes Cdkn1b/p27, Cdkn1c/p57 and Bmf. 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 number and size of tumor nodules. Conclusions: This study not only proves that miR-221 can promote liver tumorigenicity, but it also establishes a precious animal model to perform pre-clinical 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, Elisa
Primo
;
D'ABUNDO, Lucilla;FERRACIN, Manuela;BASSI, Cristian;ZAGATTI, Barbara;CORRA', Fabio;MIOTTO, Elena;LUPINI, Laura;CROCE, Carlo Maria;SABBIONI, Silvia
Penultimo
;
NEGRINI, Massimo
Ultimo
2012

Abstract

miR-221 is one of the most frequently and consistently up-regulated microRNAs in human cancer. It has been hypothesized that miR-221 may act as a tumor promoter. To fully prove it, we developed a transgenic mouse model that exhibits an inappropriate over-expression of miR-221 in the liver. Immunoblotting and immunostaining confirmed a concomitant down-regulation of miR-221 target proteins. This transgenic model is characterized by the emergence of spontaneous nodular liver lesions in about 50% of male mice and by a strong acceleration of tumor development in 100% of mice treated with diethylnitrosamine. Similarly to human HCC, tumors are characterized by a further increase in miR-221 expression and a concomitant inhibition of its target protein coding genes Cdkn1b/p27, Cdkn1c/p57 and Bmf. 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 number and size of tumor nodules. Conclusions: This study not only proves that miR-221 can promote liver tumorigenicity, but it also establishes a precious animal model to perform pre-clinical investigations for the use of anti-miRNA approaches aimed at liver cancer therapy.
Callegari, Elisa; Elamin, B. K.; Giannone, F.; Milazzo, M.; Altavilla, G.; Fornari, F.; Giacomelli, L.; D'Abundo, Lucilla; Ferracin, Manuela; Bassi, Cristian; Zagatti, Barbara; Corra', Fabio; Miotto, Elena; Lupini, Laura; Bolondi, L.; Gramantieri, L.; Croce, Carlo Maria; Sabbioni, Silvia; Negrini, Massimo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1681176
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