miR-19 is a key oncogenic component of mir-17-92
miR-19 is a key oncogenic component of mir-17-92
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DOI：
10.1101/gad.1861409
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发表时间：
2009-12-15
影响因子：
10.5
通讯作者：
He, Lin
中科院分区：
文献类型：
--
作者：
Olive, Virginie;Bennett, Margaux J.;He, Lin
近年来的研究表明，多种microRNA（miRNAs）在肿瘤发生中起重要作用，其中mir-17-92/Oncomir-1具有较强的致癌活性。mir-17-92的基因组扩增和升高的表达发生在几种人类B细胞淋巴瘤中，并且小鼠中mir-17-92的增强表达与c-myc协同促进B细胞淋巴瘤的形成。与经典的蛋白质编码癌基因不同，mir-17-92具有非常规的基因结构，其中一个初级转录物产生六个单独的miRNA。在这里，我们功能解剖的各个组成部分的mir-17-92通过分析其体内致瘤潜力。使用小鼠B细胞淋巴瘤的E mu-myc模型，我们鉴定了miR-19作为mir-17-92的关键致癌组分，其对于通过抑制凋亡促进c-myc诱导的淋巴瘤发生是必要的和充分的。miR-19的致癌活性至少部分是由于其对肿瘤抑制因子Pten的抑制。同样，miR-19激活Akt-mTOR（雷帕霉素的哺乳动物靶标）途径，从而在功能上拮抗Pten以促进细胞存活。我们的研究结果揭示了miR-19在介导mir-17-92的致癌活性中的重要作用，并暗示mir-17-92组分的功能多样性是其在肿瘤发生过程中的多效性作用的分子基础。
Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the E mu-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt-mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis.