title: Interleukin-17-induced EMT promotes lung cancer cell migration and invasion via NF-κB/ZEB1 signal pathway.
abstract: 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.
authors.affiliation: Department of Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
authors.forename: Kuo
authors.initials: K
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
authors.forename: Jing-Yan
authors.initials: JY
authors.lastname: Cao
authors.affiliation: Department of Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University Harbin, Heilongjiang 150081, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
keywords: Interleukin-17; NF-κB; ZEB1; epithelial-mesenchymal transitions; lung cancer