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

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.