Hypoxia Causes Downregulation of Dicer in Hepatocellular Carcinoma, Which Is Required for Upregulation of Hypoxia-Inducible Factor 1α and Epithelial-Mesenchymal Transition
Hypoxia Causes Downregulation of Dicer in Hepatocellular Carcinoma, Which Is Required for Upregulation of Hypoxia-Inducible Factor 1α and Epithelial-Mesenchymal Transition
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DOI：
10.1158/1078-0432.ccr-16-1762
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发表时间：
2017-07-15
影响因子：
11.5
通讯作者：
Piiper, Albrecht
中科院分区：
文献类型：
--
作者：
Ibrahim, Ahmed Atef;Schmithals, Christian;Piiper, Albrecht
目的：Dicer将前体miRNA转化为成熟miRNA，其在缺氧的肿瘤促进作用中的作用目前在一些肿瘤实体中出现。实验设计：用诱导型Dicer表达载体稳定转染HepG 2和Huh-7细胞，并暴露于缺氧/常氧。在裸鼠中建立HepG 2-Dicer异种移植物;在HCC异种移植物和来自具有内源性肝癌发生的小鼠的HCC中检测缺氧区域和Dicer;并通过免疫组织化学或免疫印迹分析上皮-间质转化（EMT）标志物。Dicer与缺氧标志物碳酸酐酶9（carbonic anhydrase 9，CA 9）的相关性在切除的人HCC中进行了研究。结果：缺氧增加了体外和体内EMT标志物，并导致HCC细胞中Dicer的下调。Dicer在内源性肝癌小鼠和HepG 2异种移植瘤中的缺氧肿瘤区域中的水平下调。在人HCC中，Dicer的水平与CA 9的水平负相关，表明缺氧对Dicer的负调节也适用于HCC患者。强制表达的Dicer防止缺氧诱导的增加缺氧诱导因子1 α（HIF 1 α），HIF 2 α，缺氧诱导基因（CA 9，葡萄糖转运蛋白1），EMT标记，和cell migration.Conclusions：我们在这里确定下调Dicer作为新的必要过程中缺氧诱导的EMT在肝癌和证明，诱导表达的Dicer抵消缺氧诱导的EMT。因此，靶向低氧诱导的Dicer下调是减少HCC进展的有希望的新策略。(C)2017年AACR。
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; and 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 downregulated 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 1 alpha (HIF1 alpha), HIF2 alpha, hypoxia-inducible genes (CA9, glucose transporter 1), EMT markers, and cell migration.Conclusions: We here identify downmodulation 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 downmodulation of Dicer is a promising novel strategy to reduce HCC progression. (C) 2017 AACR.