Gu Kuo, Li Ming-Ming, Shen Jing, Liu Fang, Cao Jing-Yan, Jin Shi, Yu Yan
Department of Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
Department of Anesthesiology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
Am J Cancer Res. 2015 Feb 15;5(3):1169-79. eCollection 2015.
Inflammatory cytokine interleukin-17 (IL-17) has been associated with the risk of progressive cancers including lung cancer. However, it remains unclear how IL-17 may contribute to the invasion and development of these inflammation-associated malignancies. Here we aimed to investigate the role of IL-17 in lung cancer cell development. Epithelial-mesenchymal transition (EMT) has been recently proposed as a developmental process which plays an important role in cancer progression and metastases. Here we show that IL-17 might promote EMT in lung cancer cells by inducing the transcriptional repressor ZEB1. Exposure to IL-17 upregulated the signature EMT phenotypic markers vimentin and E-cadherin in lung cancer cells, and compared with controls, increased cell migration was observed in IL-17-treated lung cancer cells. ZEB1 mRNA and protein expression was induced by IL-17, and IL-17 stimulated nuclear localization of phosphorylated ZEB1. Conversely, suppressing ZEB1 expression by ZEB1 siRNA abrogated IL-17-stimulated vimentin expression and cell migration. Moreover, the phosphorylation of IκBα was required for IL-17-induced expression of ZEB1, suggesting the involvement of canonical NF-κB signaling. To check this hypothesis, we used IKK inhibitor BAY 11-7028 to block NF-κB activity. We found that BAY 11-7028 abrogated IL-17-induced ZEB1 expression, cell migration, and EMT, thus confirming that NF-κB is required for IL-17 to induce these aggressive phenotypes in lung cancer cells. Taken together, our data support the idea that IL-17-induced EMT promotes lung cancer cell migration and invasion via NF-κB-mediated upregulation of ZEB1. This study reveals a new signaling axis through which the tumor microenvironment causes ZEB1 expression to promote cancer metastasis. We suggest that targeting IL-17-induced ZEB1 expression may offer an effective therapeutic strategy for lung cancer treatment.
炎性细胞因子白细胞介素-17（IL-17）与包括肺癌在内的进展性癌症风险相关。然而，IL-17如何促进这些炎症相关恶性肿瘤的侵袭和发展仍不清楚。在此，我们旨在研究IL-17在肺癌细胞发展中的作用。上皮-间质转化（EMT）最近被认为是一个在癌症进展和转移中起重要作用的发育过程。在此我们表明，IL-17可能通过诱导转录抑制因子ZEB1来促进肺癌细胞中的EMT。暴露于IL-17可上调肺癌细胞中标志性的EMT表型标志物波形蛋白和E-钙黏蛋白，并且与对照组相比，在经IL-17处理的肺癌细胞中观察到细胞迁移增加。IL-17诱导ZEB1的mRNA和蛋白表达，并且IL-17刺激磷酸化ZEB1的核定位。相反，用ZEB1 siRNA抑制ZEB1表达可消除IL-17刺激的波形蛋白表达和细胞迁移。此外，IL-17诱导的ZEB1表达需要IκBα的磷酸化，提示经典NF-κB信号通路参与其中。为验证这一假设，我们使用IKK抑制剂BAY 11-7028来阻断NF-κB活性。我们发现BAY 11-7028可消除IL-17诱导的ZEB1表达、细胞迁移和EMT，从而证实NF-κB是IL-17在肺癌细胞中诱导这些侵袭性表型所必需的。综上所述，我们的数据支持这样的观点，即IL-17诱导的EMT通过NF-κB介导的ZEB1上调促进肺癌细胞迁移和侵袭。这项研究揭示了一个新的信号轴，肿瘤微环境通过该信号轴导致ZEB1表达以促进癌症转移。我们认为，靶向IL-17诱导的ZEB1表达可能为肺癌治疗提供一种有效的治疗策略。
