Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors.
Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors.
复制标题
DOI：
10.1158/0008-5472.can-09-3970
复制
发表时间：
2010-06-01
期刊：
影响因子：
11.2
通讯作者：
Lalli E
中科院分区：
文献类型：
--
作者：
Doghman M;El Wakil A;Cardinaud B;Thomas E;Wang J;Zhao W;Peralta-Del Valle MH;Figueiredo BC;Zambetti GP;Lalli E
微小RNA（miRNAs）在转录后水平起作用，以控制几乎所有生物过程（包括肿瘤发生）中的基因表达。在这里，我们报告了一组在儿童肾上腺皮质肿瘤中差异调节的miRNA的鉴定，包括miR-99 a和miR-100。对这些miRNAs在肾上腺皮质肿瘤细胞系中的功能分析表明，它们通过3′ UTR中的结合位点协调调节IGF-mTOR-raptor信号通路的表达。在这些细胞中，活性Ser 2448-磷酸化形式的mTOR仅存在于有丝分裂细胞中，与细胞周期的G2/M期的有丝分裂纺锤体和中间体相关。依维莫司对mTOR信号传导的药理学抑制在体外和体内大大降低了肿瘤细胞生长。我们的研究结果揭示了一种新的mTOR信号调节机制的miRNAs，他们奠定了基础的mTOR通路药物治疗肾上腺皮质癌的临床评价。
MicroRNAs (miRNAs) act at the post-transcriptional level to control gene expression in virtually every biological process, including oncogenesis. Here we report the identification of a set of miRNAs that are differentially regulated in childhood adrenocortical tumors, including miR-99a and miR-100. Functional analysis of these miRNAs in adrenocortical tumor cell lines showed that they coordinately regulate expression of the IGF-mTOR-raptor signalling pathway through binding sites in their 3′ UTRs. In these cells, the active Ser2448-phosphorylated form of mTOR is present only in mitotic cells in association with the mitotic spindle and midbody in the G2/M phases of the cell cycle. Pharmacological inhibition of mTOR signalling by everolimus greatly reduces tumor cell growth in vitro and in vivo. Our results reveal a novel mechanism of regulation of mTOR signalling by miRNAs, and they lay the groundwork for clinical evaluation of mTOR pathway drugs for treatment of adrenocortical cancer.