Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer
Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer
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DOI：
10.1016/j.bbrc.2014.11.014
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发表时间：
2014-12-12
影响因子：
3.1
通讯作者：
Takahashi, Kazuhisa
中科院分区：
文献类型：
--
作者：
Nurwidya, Fariz;Takahashi, Fumiyuki;Takahashi, Kazuhisa
胰岛素样生长因子1受体（IGF1R）在包括非小细胞肺癌（NSCLC）在内的许多类型的实体肿瘤中表达，IGF1R激活增强被认为反映了癌症的进展。上皮-间质转化（Epithelial-mesenchymal transition， EMT）已被确定为癌症进展和转移的机制之一，微环境条件（如缺氧）已被证明可诱导EMT。本研究的目的是探讨IGF1R激活在NSCLC缺氧诱导的EMT中的作用，并确定抑制IGF1R是否可以逆转缺氧诱导的EMT。我们将人NSCLC细胞系A549和HCC2935暴露于缺氧环境下，研究emt相关基因的表达和表型。通过实时荧光定量PCR分析基因表达，通过形态学评估、抓痕实验和免疫荧光研究细胞表型。缺氧暴露的细胞呈现纺锤形形态，细胞运动性增加，使人联想到EMT，并表现出e-钙粘蛋白的缺失和纤维连接蛋白和波形蛋白的表达增加。缺氧也导致IGF1、IGF结合蛋白-3 （IGFBP3）和IGF1R的表达增加，但不影响转化生长因子β 1 （TGF β 1）的表达。YC-1抑制缺氧诱导因子1 α (HIF1 α)可抑制IGF1R的激活，并降低缺氧细胞中IGF1和IGFBP3的表达。此外，在缺氧条件下，AEW541抑制IGF1R可以恢复E-cadherin的表达，并降低纤维连接蛋白和vimentin的表达。最后，IGF1刺激常氧细胞诱导EMT。我们的研究结果表明，缺氧通过激活IGF1R诱导NSCLC细胞EMT，而IGF1R抑制逆转了这一现象。这些结果表明，靶向IGF1R在预防缺氧诱导的EMT介导的癌症进展和转移中具有潜在的作用。(C) 2014爱思唯尔公司版权所有。
Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid tumors including non-small cell lung cancer (NSCLC), and enhanced activation of IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition (EMT) has been established as one of the mechanisms responsible for cancer progression and metastasis, and microenvironment conditions, such as hypoxia, have been shown to induce EMT. The purposes of this study were to address the role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines A549 and HCC2935 were exposed to hypoxia to investigate the expression of EMT-related genes and phenotypes. Gene expression analysis was performed by quantitative real-time PCR and cell phenotypes were studied by morphology assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells exhibited a spindle-shaped morphology with increased cell motility reminiscent of EMT, and demonstrated the loss of E-cadherin and increased expression of fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor beta 1 (TGF beta 1). Inhibition of hypoxia-inducible factor 1 alpha (HIF1 alpha) with YC-1 abrogated activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored E-cadherin expression, and reduced expression of fibronectin and vimentin. Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that IGF1R inhibition reversed these phenomena. These results suggest a potential role for targeting IGF1R in the prevention of hypoxia-induced cancer progression and metastasis mediated by EMT. (C) 2014 Elsevier Inc. All rights reserved.