Adenosine triphosphate-binding cassette transporter genes up-regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs
Adenosine triphosphate-binding cassette transporter genes up-regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs
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DOI：
10.1002/hep.24682
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发表时间：
2012-03-01
期刊：
影响因子：
13.5
通讯作者：
Konstantinova, Pavlina
中科院分区：
文献类型：
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作者：
Borel, Florie;Han, Ruiqi;Konstantinova, Pavlina
三磷酸腺苷（ATP）结合盒（ABC）转运蛋白是导致肝细胞癌（HCC）治疗失败的多药耐药表型的药物外排泵。在这里，我们研究了19对HCC患者样本（16例未经治疗，3例接受化疗）中与多药耐药相关的15种ABC转运蛋白的表达。与邻近健康肝脏相比，12个ABC转运蛋白在HCC中表达上调。这些包括ABCA 2、ABCB 1、ABCB 6、ABCC 1、ABCC 2、ABCC 3、ABCC 4、ABCC 5、ABCC 10、ABCC 11、ABCC 12和ABCE 1。迄今为止，这些转运蛋白中的一些的表达谱和功能与HCC无关。由于细胞微小RNA（miRNA）参与转录后基因沉默，我们假设肝癌中ABC表达的调节可能是由miRNA介导的。为了研究这一点，我们对miRNAs进行了分析，与健康肝脏相比，HCC中有90种miRNAs表达异常，包括11种上调和79种下调。ABC基因中的miRNA靶位点通过荧光素酶报告基因测定进行生物信息学预测和体外实验验证。总共有13种细胞miRNA被证实靶向ABCA 1、ABCC 1、ABCC 5、ABCC 10和ABCE 1基因并介导基因表达的变化。个体患者ABC和miRNA表达之间的相关性分析揭示了负相关关系，为HCC中ABC基因的miRNA调控提供了指示。结论：肝癌组织中ABC转运蛋白的表达上调发生在化疗前，并与miRNA表达下调相关。在HCC患者样本中，5个ABC基因的上调似乎由13种细胞miRNA介导。基于miRNA的基因治疗可能是一种新的和有前途的方式来影响ABC谱和克服临床多药耐药。（肝病学2012）
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are drug efflux pumps responsible for the multidrug resistance phenotype causing hepatocellular carcinoma (HCC) treatment failure. Here we studied the expression of 15 ABC transporters relevant for multidrug resistance in 19 paired HCC patient samples (16 untreated, 3 treated by chemotherapeutics). Twelve ABC transporters showed up-regulation in HCC compared with adjacent healthy liver. These include ABCA2, ABCB1, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC10, ABCC11, ABCC12, and ABCE1. The expression profile and function of some of these transporters have not been associated with HCC thus far. Because cellular microRNAs (miRNAs) are involved in posttranscriptional gene silencing, we hypothesized that regulation of ABC expression in HCC might be mediated by miRNAs. To study this, miRNAs were profiled and dysregulation of 90 miRNAs was shown in HCC compared with healthy liver, including up-regulation of 11 and down-regulation of 79. miRNA target sites in ABC genes were bioinformatically predicted and experimentally verified in vitro using luciferase reporter assays. In total, 13 cellular miRNAs were confirmed that target ABCA1, ABCC1, ABCC5, ABCC10, and ABCE1 genes and mediate changes in gene expression. Correlation analysis between ABC and miRNA expression in individual patients revealed an inverse relationship, providing an indication for miRNA regulation of ABC genes in HCC. Conclusion: Up-regulation of ABC transporters in HCC occurs prior to chemotherapeutic treatment and is associated with miRNA down-regulation. Up-regulation of five ABC genes appears to be mediated by 13 cellular miRNAs in HCC patient samples. miRNA-based gene therapy may be a novel and promising way to affect the ABC profile and overcome clinical multidrug resistance. (Hepatology 2012)