NF-κB-mediated inflammation leading to EMT via miR-200c is involved in cell transformation induced by cigarette smoke extract.
NF-κB-mediated inflammation leading to EMT via miR-200c is involved in cell transformation induced by cigarette smoke extract.
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DOI：
10.1093/toxsci/kft150
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发表时间：
2013-10
期刊：
影响因子：
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通讯作者：
Yue Zhao;Yuan Xu;Yuan Li;Wenchao Xu;Fei Luo;Bairu Wang;Y. Pang;Q. Xiang;Jianwei Zhou;
中科院分区：
文献类型：
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作者：
Yue Zhao;Yuan Xu;Yuan Li;Wenchao Xu;Fei Luo;Bairu Wang;Y. Pang;Q. Xiang;Jianwei Zhou;
吸烟对人类健康构成重大危害，因为它是肺癌最重要的危险因素。虽然吸烟诱发人类肺癌的证据是强有力的，但吸烟导致癌症的分子机制仍有待建立。在这项研究中，我们评估了炎症和上皮间质转化（EMT）在香烟烟雾提取物（CSE）诱导的人支气管上皮（HBE）细胞转化中的作用。结果表明，CSE慢性暴露可诱导这些细胞发生EMT和转化。CSE激活核因子-κB（NF-κB）可增加促炎性白细胞介素-6（IL-6）水平，急性和慢性暴露于CSE可导致miR-200 c水平降低。通过Bay 11 -7082阻断NF-κB、抗IL-6抗体阻断IL-6、重组人IL-6增强IL-6，我们发现NF-κB信号通路参与了CSE诱导的IL-6升高，从而抑制miR-200 c表达，促进EMT。此外，IL-6是维持CSE诱导的转化和HBE细胞恶性进展所必需的。最后，用Bay 11 -7082阻断NF-κB可防止CSE诱导的EMT和恶性转化，这是由于E-cadherin和miR-200 c减少以及IL-6、N-cadherin和波形蛋白升高所致。因此，我们已经确定了炎症和EMT之间的联系，EMT是由CSE引起的细胞恶性转化过程。通过miRNAs介导的这种联系建立了CSE诱导的肺癌发生机制。
Cigarette smoking constitutes a major human health hazard because it is the most important risk factor for lung cancer. Although evidence for smoking-induced lung cancer in humans is strong, the molecular mechanisms by which smoking causes cancer remain to be established. In this investigation, we evaluated the roles of inflammation and the epithelial-mesenchymal transition (EMT) in cigarette smoke extract (CSE)-induced transformation of human bronchial epithelial (HBE) cells. The results showed that chronic exposure to CSE induced EMT and transformation of these cells. Activation of nuclear factor-κB (NF-κB) by CSE increased levels of the proinflammatory interleukin-6 (IL-6), and acute and chronic exposures to CSE caused decreases in miR-200c levels. By blocking NF-κB with Bay11-7082 and IL-6 with anti-IL-6 antibody and enhancement of IL-6 with human recombinant IL-6, we found that the NF-κB signal pathway was involved in CSE-induced increases of IL-6, which suppressed miR-200c expression and promoted EMT. Moreover, IL-6 was necessary for maintenance of CSE-induced transformation and for malignant progression of HBE cells. Finally, blocking of NF-κB with Bay11-7082 prevented CSE-induced EMT and malignant transformation due to decreases of E-cadherin and miR-200c and elevations of IL-6, N-cadherin, and vimentin. Thus, we have defined a link between inflammation and EMT, processes involved in the malignant transformation of cells caused by CSE. This link, mediated through miRNAs, establishes a mechanism for CSE-induced lung carcinogenesis.