Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2.
Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2.
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DOI：
10.1158/1535-7163.mct-09-0292
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发表时间：
2009-10
影响因子：
5.7
通讯作者：
Bates SE
中科院分区：
文献类型：
--
作者：
To KK;Robey RW;Knutsen T;Zhan Z;Ried T;Bates SE
ABCG 2的过表达已经在选择用于耐药性的细胞系中被报道，并且广泛认为其在抗癌药物的临床药理学中是重要的。我们和其他人先前已经鉴定并验证了两种靶向ABCG 2的microRNA（hsa-miR-519 c和hsa-miR-520 h）。在本研究中，发现ABCG 2 3′非翻译区（3′UTR）缩短是许多ABCG 2过表达耐药细胞系中的常见现象，其结果是去除了hsa-miR-519 c结合位点及其对mRNA稳定性和翻译阻断的抑制作用，从而有助于耐药。另一方面，hsa-miR-520 h的表达减少，以前认为是ABCG 2过表达，发现是由高表达的ABCG 2对microRNA的隔离引起的。在药物敏感细胞中，针对hsa-miR-519 c和hsa-miR-520 h的抑制剂可以增强米托蒽醌的细胞毒性作用，这表明两种microRNA在控制ABCG 2水平从而控制抗癌药物应答中的重要作用。然而，在耐药细胞中，改变两种microRNA的水平对米托蒽醌的敏感性没有任何影响。总之，这些研究表明，在ABCG 2过表达的耐药细胞中，hsa-miR-519 c不能影响ABCG 2表达，因为mRNA缺乏其结合位点;而hsa-miR-520 h被隔离，不能限制ABCG 2表达。鉴于最近观察到ABCG 2过表达的人胚胎干细胞中也观察到截短的3′UTR，我们在耐药细胞系中的结果表明，3′UTR截短是ABCG 2调控的一种相对常见的机制。
Overexpression of ABCG2 has been reported in cell lines selected for drug resistance and it is widely believed to be important in the clinical pharmacology of anticancer drugs. We and others have previously identified and validated two microRNAs (hsa-miR-519c and hsa-miR-520h) targeting ABCG2. In this study, the shortening of the ABCG2 3′ untranslated region (3′UTR) was found to be a common phenomenon in a number of ABCG2-overexpressing resistant cell lines, which as a result removes the hsa-miR-519c binding site and its repressive effects on mRNA stability and translation blockade, thereby contributing to drug resistance. On the other hand, reduced expression of hsa-miR-520h, previously thought to have allowed ABCG2 overexpression, was found to be caused by the sequestering of the microRNA by the highly expressed ABCG2. In drug sensitive cells, inhibitors against hsa-miR-519c and hsa-miR-520h could augment the cytotoxic effect of mitoxantrone, suggesting a substantial role for both microRNAs in controlling ABCG2 level and thereby anticancer drug response. However, in drug resistant cells, altering the levels of the two microRNAs did not have any effect on sensitivity to mitoxantrone. Taken together, these studies suggest that in ABCG2 overexpressing drug resistant cells, hsa-miR-519c, is unable to impact ABCG2 expression because the mRNA lacks its binding site; whereas hsa-miR-520h is sequestered and unable to limit ABCG2 expression. Given the recent observation that a truncated 3′UTR is also observed in ABCG2-overexpressing human embryonic stem cells, our results in drug resistant cell lines suggest that 3′UTR truncation is a relatively common mechanism of ABCG2 regulation.