MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth
MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth
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DOI：
10.1172/jci62980
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发表时间：
2013-06-01
影响因子：
15.9
通讯作者：
Markel, Gal
中科院分区：
文献类型：
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作者：
Nemlich, Yael;Greenberg, Eyal;Markel, Gal
一些实体瘤减少了腺苷脱氨酶作用于RNA（阿达尔）酶的转录后RNA编辑，但这种改变的功能意义尚不清楚。在这里，我们发现主要的RNA编辑酶ADAR 1在转移性黑色素瘤中经常减少。使用进展组织微阵列对黑色素瘤样本进行原位分析表明，在转移性转化过程中ADAR 1显著下调。此外，ADAR 1敲低改变细胞形态，促进体外增殖，并显着增强体内致瘤性。比较全基因组表达微阵列分析显示，ADAR 1控制着100多种microRNA（miRNA）的表达，这些microRNA调节着与观察到的表型相关的许多基因。重要的是，我们发现ADAR1通过let-7在翻译水平上调节Dicer表达，以RNA结合依赖性但不依赖于RNA编辑的方式从根本上调节miRNA加工。此外，ADAR 1与DGCR 8形成复合物，该复合物与在细胞核中处理pri-miRNAs的DGCR 8-Drosha复合物相互排斥。我们发现癌细胞通过过表达miR-17和miR-432来沉默ADAR 1，这两种基因都直接靶向ADAR 1转录物。我们进一步证明了编码miR-17和miR-432的基因在黑色素瘤中经常扩增，并且染色体14中印迹DLK1-DIO3区域的异常低甲基化也可以驱动miR-432过表达。
Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding-dependent, yet RNA editing-independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8-Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR-17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression.