Silencing of the miR-17~92 cluster family inhibits medulloblastoma progression

摘要

Medulloblastoma (MB), originating in the cerebellum, is the most common malignant brain tumor in children. MB consists of four major groups where constitutive activation of the Sonic Hedgehog (SHH) signaling pathway is a hallmark of one group. Mouse and human SHH MBs exhibit increased expression of microRNAs encoded by the miR-17~92 and miR-106b~25 clusters compared to granule progenitors and post-mitotic granule neurons. Here, we assessed the therapeutic potential of 8-mer seed-targeting LNA-modified antimiR oligonucleotides, termed tiny LNAs, that inhibit microRNA seed families expressed by miR-17~92 and miR-106b~25 in two mouse models of SHH MB. We found that tumor cells (MB cells) passively took up 8-mer LNA-antimiRs, and specifically inhibited targeted microRNA seed-sharing family members. Inhibition of miR-17 and miR-19a seed families by antimiR-17 and antimiR-19, respectively, resulted in diminished tumor cell proliferation in vitro. Treatment of mice with systemic delivery of antimiR-17 and antimiR-19 reduced tumor growth in flank and brain allografts in vivo and prolonged the survival of mice with intracranial transplants, suggesting that inhibition of the miR-17~92 cluster family by 8-mer LNA-antimiRs might be considered for the treatment of SHH MBs.