Abstract
Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and it carries a high risk of metastasis and mortality. Various proinflammatory cytokines have been found to be significantly increased in the aqueous humor or vitreous fluid of UM patients; however, the role of these cytokines in UM metastasis remains elusive. In the present study, we found that long-term interleukin (IL)-6 exposure promoted the migration and invasion of UM cells, diminished cell–cell adhesion, and enhanced focal adhesion. Moreover, IL-6 treatment decreased the membranous epithelial marker TJP1 and increased the cytoplasmic mesenchymal marker Vimentin. Further investigation demonstrated that JunB played a critical role in IL-6-induced UM epithelial–mesenchymal transition (EMT). In UM cells, the expression of JunB was significantly up-regulated during the IL-6-driven EMT process. Additionally, JunB induction occurred at the transcriptional level in a manner dependent on phosphorylated STAT3, during which activated STAT3 directly bound to the JunB promoter. Importantly, the knockdown of STAT3 prevented the IL-6-induced EMT phenotype as well as cell migration and invasion, whereas JunB overexpression recovered the attenuated aggressiveness of UM cells. Similarly, with IL-6 stimulation, the stable overexpression of JunB strengthened the migratory and invasive capabilities of UM cells and induced the EMT-promoting factors (Snail, Twist1, matrix metalloproteinase (MMP)-2, MMP-14, and MMP-19). Analysis of The Cancer Genome Atlas (TCGA) database indicated that JunB was positively correlated with IL-6 and STAT3 in UM tissues. The present study proposes an IL-6/STAT3/JunB axis leading to UM aggressiveness by EMT, which illustrates the negative side of inflammatory response in UM metastasis.
Highlights
Uveal melanoma (UM) is the most common primary ocular malignancy in adults, accounting for more than half of all eye cancers
Two well-validated UM cell lines with different morphologies were used to construct IL-6-transformed UM cells by long-term exposure to low-dose IL-6, which mimics the intraocular microenvironment of UM
IL-6-transformed UM cells were more aggressive than the parental cells, and stronger induction by IL-6 was observed in the IL6/C918 cells than in the IL6/OCM1A cells
Summary
Uveal melanoma (UM) is the most common primary ocular malignancy in adults, accounting for more than half of all eye cancers. Despite the rarity and proper treatment of the primary ocular tumor, approximately 50% of UM patients may develop lethal systemic metastases, in which the liver is the principal metastatic organ [1]. Once liver metastasis is diagnosed, the prognosis is poor, with a median survival time between 4 and 15 months [2]. Previous studies have greatly increased the knowledge of UM development, the relevant factors that contribute to metastasis are still not well known. This knowledge is urgently needed for the early detection and treatment of metastatic UM
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