MicroRNA-18a Prevents Estrogen Receptor-α Expression, Promoting Proliferation of Hepatocellular Carcinoma Cells
MicroRNA-18a Prevents Estrogen Receptor-α Expression, Promoting Proliferation of Hepatocellular Carcinoma Cells
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DOI：
10.1053/j.gastro.2008.10.029
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发表时间：
2009-02-01
期刊：
影响因子：
29.4
通讯作者：
Chen, Pei-Jer
中科院分区：
文献类型：
--
作者：
Liu, Wan-Hsin;Yeh, Shiou-Hwei;Chen, Pei-Jer
背景与目的：男性肝细胞癌（HCC）的发病率高于女性，部分原因是雌激素的保护作用。我们试图确定男性和女性 HCC 样本之间的 microRNA (miRNA) 分子水平是否存在差异。方法：使用 TaqMan miRNA 测定法比较男性和女性 HCC 组织中一组候选 miRNA 的表达谱。荧光素酶报告基因检测用于鉴定特定 miRNA 识别的 mRNA 靶标。通过定量逆转录聚合酶链式反应测定每种特定 miRNA 的 pri- 和 pre-miRNA 水平，以描绘生物发生过程中失调的步骤。最后，使用比色测定法确定特定 miRNA 对肝癌的影响。细胞增殖。结果：miR-18a miRNA 在女性 HCC 患者样本中显着增加（女性/男性比率，4.58；P = .0023）。编码雌激素受体α（ERα）的基因ESR1被确定为miR-18a的靶标。 miR-18a 可以通过在 3' 非翻译区与其 mRNA 结合来抑制 ERa 翻译。女性 HCC 组织中 miR-18a 水平升高与 ERa 表达降低相关；在这些组织中，pre-miR-18a 的水平与成熟 miR-18a 的水平变化一致。 miR-18a的过度表达降低了ERa水平，但刺激了肝癌细胞的增殖。结论：本研究提供了一种新的 miRNA 介导的调控肝细胞 ERa 表达的调控机制。 miR-18a 阻止 ERa 的翻译，可能阻断雌激素的保护作用并促进女性 HCC 的发展。
Background & Aims: Men have a higher incidence of hepatocellular carcinoma (HCC) than women, which is believed to partly be because of protective effects of estrogen. We sought to determine whether there were differences in levels of microRNA (miRNA) molecules between male and female HCC samples. Methods: The expression profiles of a panel of candidate miRNAs were compared between male and female HCC tissues using the TaqMan miRNA assay. A luciferase reporter assay was used to identify mRNA targets recognized by specific miRNAs. The levels of pri- and pre-miRNA for each specific miRNA were assayed by quantitative reverse-transcription polymerase chain reaction to delineate the step deregulated in the biogenesis process. Finally, a colorimetric assay was used to determine the effect of specific miRNAs on hepatoma. cell proliferation. Results: The miR-18a miRNA increased specifically in samples from female HCC patients (female/male ratio, 4.58; P = .0023). The gene ESR1, which encodes the estrogen receptor-alpha (ER alpha), was identified as a target of miR-18a. miR-18a can repress ERa translation by binding to its mRNA at the 3' untranslated region. Increased levels of miR-18a in female HCC tissues correlated with reduced ERa expression; the level of pre-miR-18a changed in concordance with that of mature miR-18a in these tissues. Overexpression of miR-18a decreased ERa levels but stimulated the proliferation of hepatoma cells. Conclusions: This study provides a novel miRNA-mediated regulatory mechanism for controlling ERa expression in hepatocytes. miR-18a prevents translation of ERa, potentially blocking the protective effects of estrogen and promoting the development of HCC in women.