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Sanguinarine inhibits epithelial-mesenchymal transition via targeting HIF-1α/TGF-β feed-forward loop in hepatocellular carcinoma.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-12-09 , DOI: 10.1038/s41419-019-2173-1 Qi Su 1 , Mengying Fan 1 , Jingjing Wang 1 , Asmat Ullah 1 , Mohsin Ahmad Ghauri 1 , Bingling Dai 1 , Yingzhuan Zhan 1 , Dongdong Zhang 1 , Yanmin Zhang 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-12-09 , DOI: 10.1038/s41419-019-2173-1 Qi Su 1 , Mengying Fan 1 , Jingjing Wang 1 , Asmat Ullah 1 , Mohsin Ahmad Ghauri 1 , Bingling Dai 1 , Yingzhuan Zhan 1 , Dongdong Zhang 1 , Yanmin Zhang 1
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Epithelial-mesenchymal transition (EMT) plays a crucial role in hepatocellular carcinoma (HCC) progression. Hypoxia and excessive transforming growth factor-β (TGF-β) have been identified as inducers and target for EMT in HCC. Here, we show hypoxia inducible factor-1α (HIF-1α) and TGF-β form a feed-forward loop to induce EMT in HCC cells. Further mechanistic study indicates under both hypoxia and TGF-β stimulation, Smad and PI3K-AKT pathways are activated. We show sanguinarine, a natural benzophenanthridine alkaloid, impairs the proliferation of nine kinds of HCC cell lines and the colony formation of HCC cells. In hypoxic and TGF-β cell models, sanguinarine inhibits HIF-1α signaling and the expression of EMT markers, translocation of Snail and activation of both Smad and PI3K-AKT pathways. Sanguinarine could also inhibit TGF-β-induced cell migration in HCC cells. In vivo studies reveal that the administration of sanguinarine inhibits tumor growth and HIF-1α signaling, inhibits the expression changes of EMT markers as well as Smad and PI3K-AKT pathway proteins. Our findings suggest that sanguinarine is a promising candidate targeting HIF-1α/TGF-β signaling to improve the treatment for HCC patients.
中文翻译：
血红素碱通过靶向肝细胞癌中的HIF-1α/TGF-β前馈环来抑制上皮-间质转化。
上皮-间质转化（EMT）在肝细胞癌（HCC）的进展中起着至关重要的作用。缺氧和过度转化生长因子-β（TGF-β）已被确定为肝癌EMT的诱导剂和靶标。在这里，我们显示缺氧诱导因子-1α（HIF-1α）和TGF-β形成前馈环，以诱导HCC细胞中的EMT。进一步的机理研究表明，在缺氧和TGF-β刺激下，Smad和PI3K-AKT途径均被激活。我们显示sanguinarine，一种天然的苯并菲啶生物碱，损害了9种HCC细胞系的增殖和HCC细胞的集落形成。在缺氧和TGF-β细胞模型中，sanguinarine抑制HIF-1α信号传导和EMT标记物的表达，Snail的易位以及Smad和PI3K-AKT通路的激活。血红素还可以抑制TGF-β诱导的HCC细胞迁移。体内研究表明，使用血红素碱可抑制肿瘤生长和HIF-1α信号传导，抑制EMT标记以及Smad和PI3K-AKT途径蛋白的表达变化。我们的发现表明，血红素碱是靶向HIF-1α/TGF-β信号转导的有望改善肝癌患者治疗的候选药物。
更新日期：2019-12-09
中文翻译：
血红素碱通过靶向肝细胞癌中的HIF-1α/TGF-β前馈环来抑制上皮-间质转化。
上皮-间质转化（EMT）在肝细胞癌（HCC）的进展中起着至关重要的作用。缺氧和过度转化生长因子-β（TGF-β）已被确定为肝癌EMT的诱导剂和靶标。在这里，我们显示缺氧诱导因子-1α（HIF-1α）和TGF-β形成前馈环，以诱导HCC细胞中的EMT。进一步的机理研究表明，在缺氧和TGF-β刺激下，Smad和PI3K-AKT途径均被激活。我们显示sanguinarine，一种天然的苯并菲啶生物碱，损害了9种HCC细胞系的增殖和HCC细胞的集落形成。在缺氧和TGF-β细胞模型中，sanguinarine抑制HIF-1α信号传导和EMT标记物的表达，Snail的易位以及Smad和PI3K-AKT通路的激活。血红素还可以抑制TGF-β诱导的HCC细胞迁移。体内研究表明，使用血红素碱可抑制肿瘤生长和HIF-1α信号传导，抑制EMT标记以及Smad和PI3K-AKT途径蛋白的表达变化。我们的发现表明，血红素碱是靶向HIF-1α/TGF-β信号转导的有望改善肝癌患者治疗的候选药物。
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