Hypoxia causes down-regulation of Dicer in hepatocellular carcinoma, which is required for up-regulation of hypoxia inducible factor 1α and epithelial-mesenchymal transition
Hypoxia causes down-regulation of Dicer in hepatocellular carcinoma, which is required for up-regulation of hypoxia inducible factor 1α and epithelial-mesenchymal transition
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缺氧导致肝细胞癌中 Dicer 下调，这是缺氧诱导因子 1α 上调和上皮间质转化所必需的
DOI：
10.1055/s-0036-1597476
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
A. Piiper
中科院分区：
文献类型：
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作者：
A. Ibrahim;C. Schmithals;E. Kowarz;V. Köberle;B. Kakoschky;T. Pleli;O. Kollmar;S. Nitsch;O. Waidmann;F. Finkelmeier;S. Zeuzem;HW Korf;T. Schmid;A. Weigert;B. Kronenberger;R. Marschalek;A. Piiper
目的：Dicer可将前体mirna转化为成熟mirna，目前在一些肿瘤实体中发现其在缺氧促肿瘤中的作用。它在肝细胞癌（HCC）中的作用尚不清楚。实验设计：用诱导型Dicer表达载体稳定转染HepG2和Huh-7细胞，并暴露于缺氧/常氧环境中。裸鼠建立HepG2-Dicer异种移植物；在肝癌异种移植和内源性肝癌小鼠肝癌中检测缺氧区和Dicer；采用免疫组织化学或免疫印迹法分析上皮间充质转化（EMT）标志物。Dicer与缺氧标志物碳酸酐酶9 （CA9）的相关性在切除的人类hcc中进行了研究。结果：缺氧使体外和体内EMT标志物升高，导致HCC细胞中Dicer水平下调。在内源性肝癌小鼠和HepG2异种移植小鼠的缺氧肿瘤区，Dicer水平下调。在人类HCC中，Dicer水平与CA9水平呈负相关，表明缺氧对Dicer的负调控也适用于HCC患者。强制表达Dicer可阻止缺氧诱导的缺氧诱导因子1α (HIF-1α)、缺氧诱导基因（CA9、葡萄糖转运蛋白1）、EMT标记物和细胞迁移的增加。结论：我们在此发现Dicer的下调是HCC缺氧诱导的EMT的一个新的必要过程，并证明诱导Dicer的表达抵消了缺氧诱导的EMT。因此，靶向缺氧诱导的Dicer下调是一种很有前景的减少HCC进展的新策略。
Purpose: A role of Dicer, which converts precursor miRNAs to mature miRNAs, in the tumor-promoting effect of hypoxia is currently emerging in some tumor entities. Its role in hepatocellular carcinoma (HCC) is unknown.Experimental design: HepG2 and Huh-7 cells were stably transfected with an inducible Dicer expression vector and were exposed to hypoxia/normoxia. HepG2-Dicer xenografts were established in nude mice; hypoxic areas and Dicer were detected in HCC xenografts and HCCs from mice with endogenous hepatocarcinogenesis; epithelial mesenchymal transition (EMT) markers were analyzed by immunohistochemistry or by immunoblotting. The correlation between Dicer and carbonic anhydrase 9 (CA9), a marker of hypoxia, was investigated in resected human HCCs.Results: Hypoxia increased EMT markers in vitro and in vivo and led to a downregulation of Dicer in HCC cells. The levels of Dicer were down-regulated in hypoxic tumor regions in mice with endogenous hepatocarcinogenesis and in HepG2 xenografts. In human HCCs the levels of Dicer correlated inversely with those of CA9, indicating that the negative regulation of Dicer by hypoxia also applies to HCC patients. Forced expression of Dicer prevented the hypoxia-induced increase in hypoxia inducible factor 1α (HIF-1α), hypoxia-inducible genes (CA9, glucose transporter 1), EMT markers and cell migration.Conclusions: We here identify down-modulation of Dicer as novel essential process in hypoxia-induced EMT in HCC and demonstrate that induced expression of Dicer counteracted hypoxia-induced EMT. Thus, targeting hypoxia-induced down-modulation of Dicer is a promising novel strategy to reduce HCC progression.