Ferretti Elisabetta, De Smaele Enrico, Miele Evelina, Laneve Pietro, Po Agnese, Pelloni Marianna, Paganelli Arianna, Di Marcotullio Lucia, Caffarelli Elisa, Screpanti Isabella, Bozzoni Irene, Gulino Alberto
Department of Experimental Medicine, Sapienza University, Roma, Italy.
EMBO J. 2008 Oct 8;27(19):2616-27. doi: 10.1038/emboj.2008.172. Epub 2008 Aug 28.
MicroRNAs (miRNA) are crucial post-transcriptional regulators of gene expression and control cell differentiation and proliferation. However, little is known about their targeting of specific developmental pathways. Hedgehog (Hh) signalling controls cerebellar granule cell progenitor development and a subversion of this pathway leads to neoplastic transformation into medulloblastoma (MB). Using a miRNA high-throughput profile screening, we identify here a downregulated miRNA signature in human MBs with high Hh signalling. Specifically, we identify miR-125b and miR-326 as suppressors of the pathway activator Smoothened together with miR-324-5p, which also targets the downstream transcription factor Gli1. Downregulation of these miRNAs allows high levels of Hh-dependent gene expression leading to tumour cell proliferation. Interestingly, the downregulation of miR-324-5p is genetically determined by MB-associated deletion of chromosome 17p. We also report that whereas miRNA expression is downregulated in cerebellar neuronal progenitors, it increases alongside differentiation, thereby allowing cell maturation and growth inhibition. These findings identify a novel regulatory circuitry of the Hh signalling and suggest that misregulation of specific miRNAs, leading to its aberrant activation, sustain cancer development.
微小RNA（miRNA）是基因表达至关重要的转录后调节因子，可控制细胞分化和增殖。然而，对于它们对特定发育途径的靶向作用却知之甚少。刺猬信号通路（Hh）控制小脑颗粒细胞祖细胞的发育，该通路的颠覆会导致肿瘤转化为髓母细胞瘤（MB）。通过miRNA高通量谱筛选，我们在此鉴定出具有高Hh信号的人类MB中下调的miRNA特征。具体而言，我们鉴定出miR-125b和miR-326作为通路激活因子Smoothened的抑制剂，miR-324-5p也靶向下游转录因子Gli1。这些miRNA的下调使得高水平的Hh依赖性基因表达导致肿瘤细胞增殖。有趣的是，miR-324-5p的下调是由与MB相关的17号染色体短臂缺失遗传决定的。我们还报告说，虽然miRNA表达在小脑神经元祖细胞中下调，但它随着分化而增加，从而促进细胞成熟和生长抑制。这些发现确定了Hh信号通路的一种新的调节机制，并表明特定miRNA的失调导致其异常激活，从而维持癌症发展。
