Chitin synthesis inhibitors promote liver cancer cell metastasis via interfering with hypoxia-inducible factor 1α
Chitin synthesis inhibitors promote liver cancer cell metastasis via interfering with hypoxia-inducible factor 1α
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DOI：
10.1016/j.chemosphere.2018.05.014
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发表时间：
2018-09-01
期刊：
影响因子：
8.8
通讯作者：
Sang, Nan
中科院分区：
文献类型：
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作者：
Ning, Xia;Wang, Yue;Sang, Nan
甲壳素合成抑制剂（CSI）作为传统杀虫剂的替代品，近年来在世界范围内受到广泛需求。然而，很少有人关注CSIs的潜在生态安全和健康风险，特别是它们干扰非性激素受体如缺氧诱导因子1 α（HIF-1 α）的能力。在这项工作中，我们进行了一个系统的研究，关于CSIs对HIF-1 α相关的肝癌细胞转移的影响。双荧光素酶报告基因测定显示，14种CSIs中的2种在非细胞毒性浓度下表现出剂量响应的HIF-1 α激动活性，灭幼脲（DFB）的相对荧光素酶活性（RLA）值为25.6%，杀铃脲（TFM）的相对荧光素酶活性（RLA）值为20.9%。根据该结果，体外生物测定证明DFB和TFM都刺激HepG 2细胞迁移和侵袭。这种作用与参与上皮-间质转化（EMT）活化和细胞外基质（ECM）降解的基因的不同表达水平有关，例如纤维连接蛋白（FN 1）和基质金属蛋白酶-2（MMP-2）的上调以及E-钙粘蛋白（E-cad）和金属蛋白酶组织抑制剂-2（TIMP-2）的抑制。此外，这些EMT和ECM表型标志物的变化被HIF-1 α抑制剂（KC 7 F2）显著阻断，这进一步证实了HIF-1 α参与CSI诱导的HepG 2细胞转移。我们的研究结果第一次揭示了CSIs在促进人类肝癌细胞转移中起着至关重要的作用，而HIF-1 α可能是这些变化的原因。(C)2018爱思唯尔有限公司版权所有。
Chitin synthesis inhibitors (CSIs), as alternatives to conventional insecticides, have been in worldwide demand in recent years. However, little attention has been paid to the potential ecological safety and health risks of CSIs, especially their abilities to interfere with nonsexual hormone receptors such as hypoxia-inducible factor la (HIF-1 alpha). In this work, we conducted a systematic study regarding the influence of CSIs on HIF-1 alpha-related liver cancer cell metastasis. The dual-luciferase reporter gene assay revealed that two of fourteen CSIs exhibited dose-response HIF-1 alpha agonistic activities at noncytotoxic concentrations with relative luciferase activity (RLA) values of 25.6% for diflubenzuron (DFB) and 20.9% for triflumuron (TFM). Following this result, in vitro bioassays demonstrated that both DFB and TFM stimulated HepG2 cell migration and invasion. This action was associated with the varied expression levels of genes involved in epithelial-to-mesenchymal transition (EMT) activation and extracellular matrix (ECM) degradation, such as the upregulation of fibronectin (FN1) and matrix metalloproteinase-2 (MMP-2) and the suppression of E-cadherin (E-cad) and tissue inhibitor of metalloproteinases-2 (TIMP2). Moreover, changes in these EMT and ECM phenotype markers were dramatically blocked by a HIF-1 alpha inhibitor (KC7F2), which further verified the involvement of HIF-1 alpha in CSI-induced HepG2 cell metastasis. For the first time, our findings reveal that CSIs play crucial roles in promoting the metastasis of human liver cancer cells and that HIF-1 alpha is potentially responsible for these changes. (C) 2018 Elsevier Ltd. All rights reserved.