miR-579-3p controls melanoma progression and resistance to target therapy
miR-579-3p controls melanoma progression and resistance to target therapy
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DOI：
10.1073/pnas.1607753113
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发表时间：
2016-08-23
影响因子：
11.1
通讯作者：
Ciliberto, Gennaro
中科院分区：
文献类型：
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作者：
Fattore, Luigi;Mancini, Rita;Ciliberto, Gennaro
对携带BRAF（V - raf鼠肉瘤病毒癌基因同源物B1）癌基因激活突变的黑色素瘤患者采用BRAF和MEK抑制剂联合治疗受到耐药性产生的困扰。突变事件以及适应性机制都促使了耐药性的发展。在此背景下，我们在此揭示了一种微小RNA（miRNA），即miR - 579 - 3p的作用。我们首先表明，miR - 579 - 3p的低表达是一个与不良生存相关的负面预后因素。miR - 579 - 3p的表达水平从痣到III/IV期黑色素瘤样本逐渐降低，在对BRAF/MEK抑制剂耐药的细胞系中甚至更低。从机制上讲，我们证明miR - 579 - 3p通过靶向两种癌蛋白（BRAF和一种E3泛素蛋白连接酶MDM2）的3'非翻译区（3'UTR）而起到抑癌作用。此外，miR - 579 - 3p的异位表达会削弱人黑色素瘤细胞耐药性的形成。最后，在对靶向治疗产生耐药性前后的患者匹配肿瘤样本中，miR - 579 - 3p都被强烈下调。
Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that lowexpression ofmiR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3'UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies.