Elevated p53 promotes the processing of miR-18a to decrease estrogen receptor-α in female hepatocellular carcinoma
Elevated p53 promotes the processing of miR-18a to decrease estrogen receptor-α in female hepatocellular carcinoma
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DOI：
10.1002/ijc.29052
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发表时间：
2015-02-15
影响因子：
6.4
通讯作者：
Yeh, Shiou-Hwei
中科院分区：
文献类型：
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作者：
Li, Chiao-Ling;Yeh, Kun-Huei;Yeh, Shiou-Hwei
长期以来，雌激素途径一直被认为是女性乙肝病毒(HBV)相关性肝细胞癌(HCC)的肿瘤保护者。我们先前的研究发现，雌激素受体α(ER)蛋白在60%的女性肝细胞癌中下调，这是通过miR-18a上调介导的ER翻译抑制而实现的。本研究旨在阐明女性肝细胞癌miR-18a表达上调的机制。对77例女性肝癌标本的分析表明，miR-18a水平与前miR-18a水平相关，而不是pri-miR-18a水平，这表明Pri-to-Pre-miR-18a的加工增强。在参与microRNA加工的一系列因素中，p53被确定为miR-18a成熟过程的新调节因子。通过si-RNA敲除P53可降低miR-18a的表达水平，而野生型或突变型P53的过表达则增加miR-18a的表达水平。在乙肝相关女性肝细胞癌的临床标本中，证实miR-18a的升高与P53的积聚有关，这主要是由体细胞突变引起的。通过与临床病理特征的相关性分析，P53/miR-18a通路的激活主要发生在年轻或非肝硬变的女性肝细胞癌患者中，并与总体生存不良的趋势有关。因此，本研究证明了上调/突变的p53通过促进miR-18a的生物发生来调节ER蛋白的量的新功能，这可能导致雌激素途径在女性肝癌发生中的肿瘤保护作用。患肝癌的男性比女性多，部分原因是雌激素途径的保护作用。许多患上肝细胞癌的女性雌激素受体较少，这是因为miR-18a水平较高，从而减缓了雌激素受体的产生。在这篇论文中，作者问，是什么导致miR-18a的增加？他们发现，p53参与了miR-18a的泵出，进一步的研究发现，捆绑p53会降低miR-18a的水平，而过度表达p53会增加miR-18a的水平。从女性肝癌患者身上采集的样本证实了这种联系，表明P53可能是女性肝癌的有用治疗靶点。
The estrogen pathway has long been implicated as a tumor protector in female hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Our previous study identified that estrogen receptor alpha (ER) protein is downregulated in 60% of female HCC cases, via a miR-18a elevation mediated suppression of ER translation. This study aims to delineate the mechanism underlying the upregulation of miR-18a in female HCC. The analysis of 77 female HCC specimens revealed that miR-18a levels were associated with pre-miR-18a rather than pri-miR-18a levels, suggesting an enhanced processing of pri- to pre-miR-18a. Among a panel of factors involved in microRNA processing, p53 was identified as a novel regulator for miR-18a maturation process. Knockdown of p53 by si-RNA decreased the level of miR-18a, whereas overexpression of either wild-type or mutant p53 increased its level. The association between the elevation of miR-18a and the accumulation of p53, mainly caused by somatic mutations, was confirmed in the clinical specimens of HBV-related female HCC. By analyzing the association with clinicopathological features, activation of this p53/miR-18a pathway mainly occurs in younger or noncirrhosis female HCC patients and associated with a trend of worse overall survival. Therefore, this study demonstrated a novel function of elevated/mutant p53 in regulating the amount of ER protein through its promoting the biogenesis of miR-18a, which could lead to decrease the tumor-protective function of the estrogen pathway in female hepatocarcinogenesis.What's new? More men than women get liver cancer, in part because of the protective effect of the estrogen pathway. Many women who do develop hepatocellular cancer have less estrogen receptor due to higher levels of miR-18a, which slows estrogen receptor production. In this paper, the authors asked, what causes the increase in miR-18a? They found that p53 participates in pumping out miR-18a, and further investigation revealed that tying up p53 decreased levels of miR-18a, while overexpressing p53 increased miR-18a. Samples taken from female HCC patients confirmed this association, suggesting that p53 could be a useful therapeutic target in female HCC.