Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation.
Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation.
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DOI：
10.1371/journal.pone.0011397
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发表时间：
2010-07-01
期刊：
影响因子：
3.7
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Yan D;Ng WL;Zhang X;Wang P;Zhang Z;Mo YY;Mao H;Hao C;Olson JJ;Curran WJ;Wang Y
放射治疗通过诱导DNA双链断裂（DSB）杀死肿瘤细胞。然而，肿瘤的有效修复经常阻碍成功的治疗。因此，确定新的实用增敏剂是走向成功的放射治疗的重要一步。在这项研究中，我们测试了新的假设：鉴定靶向DNA DSB修复基因的miRNA可能是使肿瘤对电离辐射敏感的新方法。在这里，我们选择了两个基因：以DNA-PKcs（非同源末端连接修复的关键因子）和ATM（促进同源重组修复的重要检查点调节因子）为靶点，寻找其调控miRNAs。通过结合数据库搜索和实验室工作，我们挑选出了miR-101。我们发现miR-101可以通过与DNA-PKcs或ATM mRNA的3′- UTR结合而有效靶向DNA-PKcs和ATM。上调miR-101有效地降低了这些肿瘤细胞中DNA-PKcs和ATM的蛋白水平，最重要的是，在体外和体内使肿瘤细胞对辐射敏感。这些数据首次证明了miRNAs可用于靶向DNA修复基因，从而使肿瘤对辐射敏感。这些结果为提高肿瘤的放射治疗水平提供了新的途径。
Radiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of tumors frequently prevents successful treatment. Therefore, identifying new practical sensitizers is an essential step towards successful radiotherapy. In this study, we tested the new hypothesis: identifying the miRNAs to target DNA DSB repair genes could be a new way for sensitizing tumors to ionizing radiation. Here, we chose two genes: DNA-PKcs (an essential factor for non-homologous end-joining repair) and ATM (an important checkpoint regulator for promoting homologous recombination repair) as the targets to search their regulating miRNAs. By combining the database search and the bench work, we picked out miR-101. We identified that miR-101 could efficiently target DNA-PKcs and ATM via binding to the 3′- UTR of DNA-PKcs or ATM mRNA. Up-regulating miR-101 efficiently reduced the protein levels of DNA-PKcs and ATM in these tumor cells and most importantly, sensitized the tumor cells to radiation in vitro and in vivo. These data demonstrate for the first time that miRNAs could be used to target DNA repair genes and thus sensitize tumors to radiation. These results provide a new way for improving tumor radiotherapy.
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影响因子：
4.8
作者：
Chen, Benjamin P. C.;Uematsu, Naoya;Chen, David J.
通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1073/pnas.0808042106
发表时间：
2009-03-03
影响因子：
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作者：
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作者：
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影响因子：
10.5
作者：
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