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首页> 外文期刊>Molecular and Cellular Biology >Regulation of ABCG2 Expression at the 3′ Untranslated Region of Its mRNA through Modulation of Transcript Stability and Protein Translation by a Putative MicroRNA in the S1 Colon Cancer Cell Line
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Regulation of ABCG2 Expression at the 3′ Untranslated Region of Its mRNA through Modulation of Transcript Stability and Protein Translation by a Putative MicroRNA in the S1 Colon Cancer Cell Line

机译：通过调节转录本稳定性和推定的microRNA在S1结肠癌细胞系中的蛋白质翻译，调节ABCG2在其mRNA 3'非翻译区的表达。

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ABCG2 is recognized as an important efflux transporter in clinical pharmacology and is potentially important in resistance to chemotherapeutic drugs. To identify epigenetic mechanisms regulating ABCG2 mRNA expression at its 3′ untranslated region (3′UTR), we performed 3′ rapid amplification of cDNA ends with the S1 parental colon cancer cell line and its drug-resistant ABCG2-overexpressing counterpart. We found that the 3′UTR is >1,500 bp longer in parental cells and, using the miRBase TARGETs database, identified a putative microRNA (miRNA) binding site, distinct from the recently reported hsa-miR520h site, in the portion of the 3′UTR missing from ABCG2 mRNA in the resistant cells. We hypothesized that the binding of a putative miRNA at the 3′UTR of ABCG2 suppresses the expression of ABCG2. In resistant S1MI80 cells, the miRNA cannot bind to ABCG2 mRNA because of the shorter 3′UTR, and thus, mRNA degradation and/or repression on protein translation is relieved, contributing to overexpression of ABCG2. This hypothesis was rigorously tested by reporter gene assays, mutational analysis at the miRNA binding sites, and forced expression of miRNA inhibitors or mimics. The removal of this epigenetic regulation by miRNA could be involved in the overexpression of ABCG2 in drug-resistant cancer cells.
机译：ABCG2在临床药理学中被认为是重要的外排转运蛋白，并且在对化学治疗药物的耐药性中可能潜在重要。为了鉴定调节ABCG2 mRNA在其3'非翻译区（3'UTR）的表观遗传机制，我们用S1亲代结肠癌细胞系及其耐药ABCG2过表达对应物对cDNA末端进行了3'快速扩增。我们发现在亲代细胞中3'UTR的时间长了1,500 bp，并且使用miRBase TARGETs数据库在3'的部分中确定了一个与最近报道的hsa-miR520h位点不同的推定的microRNA（miRNA）结合位点耐药细胞中ABCG2 mRNA中缺少UTR。我们假设，假定的miRNA在ABCG2的3'UTR处的结合会抑制ABCG2的表达。在耐药的S1MI80细胞中，由于3'UTR较短，miRNA无法与ABCG2 mRNA结合，因此，mRNA的降解和/或蛋白翻译的抑制得以缓解，从而导致ABCG2的过表达。通过记者基因检测，miRNA结合位点的突变分析以及miRNA抑制剂或模拟物的强制表达，对这一假设进行了严格的检验。 miRNA去除这种表观遗传调控可能与耐药癌细胞中ABCG2的过表达有关。

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