Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
Horm Cancer. 2011 Jun;2(3):182-9. doi: 10.1007/s12672-011-0072-8.
Glucocorticoids (GCs) are widely used in the treatment of hematological malignancies such as multiple myeloma. However, the development of resistance to GCs limits their clinical utility. Response to GCs is dependent on an active glucocorticoid receptor, GR-α, expressed at wild-type levels in the GC-sensitive cell line (MM.1S). GC-resistant derivative cell lines MM.1Re and MM.1RL display significant downregulation of GR-α transcripts. In this study, we report that a luciferase reporter containing the 3'-UTR of GR-α is significantly repressed in MM.1R cells when compared to MM.1S cells, suggesting that one or several microRNAs that are upregulated in MM.1R maybe in part responsible for the downregulation of the GR-α transcript. To examine posttranscriptional mechanisms of GR regulation, we examined miRNAs that have complimentary binding sites in the 3'-UTR of GR-α and found miR-130b, miR-181a, and miR-636 to be differentially expressed between GC-sensitive and GC-resistant MM.1 cell lines. Overexpression of miR-130b in MM.1S cells results in decreased expression of endogenous GR protein and decreased activity of the luciferase reporter. In addition, in MM.1S cells, the downstream GC response of glucocorticoid-induced leucine zipper induction is decreased by the overexpression of miR-130b, and further miR-130b inhibits GC-induced apoptosis and causes resistance to GCs.
糖皮质激素（GCs）广泛用于治疗多发性骨髓瘤等血液系统恶性肿瘤。然而，GC 耐药性的发展限制了它们的临床应用。GC 的作用依赖于野生型水平表达的活性糖皮质激素受体（GR-α），在 GC 敏感的细胞系（MM.1S）中表达。GC 耐药的衍生细胞系 MM.1Re 和 MM.1RL 显示 GR-α 转录本显著下调。在这项研究中，我们报告说，与 MM.1S 细胞相比，含有 GR-α 3'-UTR 的荧光素酶报告基因在 MM.1R 细胞中受到显著抑制，这表明在 MM.1R 中上调的一个或几个 microRNAs 可能部分负责 GR-α 转录本的下调。为了研究 GR 调节的转录后机制，我们检查了在 GR-α 3'-UTR 中具有互补结合位点的 microRNAs，并发现 miR-130b、miR-181a 和 miR-636 在 GC 敏感和 GC 耐药 MM.1 细胞系之间表达差异。在 MM.1S 细胞中过表达 miR-130b 导致内源性 GR 蛋白表达降低和荧光素酶报告基因活性降低。此外，在 MM.1S 细胞中，miR-130b 的过表达降低了 GC 诱导的亮氨酸拉链诱导的下游 GC 反应，并且进一步 miR-130b 抑制 GC 诱导的细胞凋亡并导致对 GCs 的耐药性。
