Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial–mesenchymal transition

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.

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Although STAT1 is known to be involved in mediating the anti-tumor immunity and other STAT families are known to be involved in the promotion of cancer development, it is STAT3 that is most well studied as a significant intrinsic transcription factor in the induction of the EMT and in the pathogenesis of cancer ( Figure 2) [16]. IL-6/JAK2/STAT3 activation enhances metastasis via induction of EMT by the upregulation of EMT-inducing transcription factors (EMT-TFs; Snail, Zeb1, JUNB, and Twist-1) and increases cell motility via focal adhesion kinase (FAK) activation [17][18][19][20]. In prostate cancer, paracrine IL-6/JAK2/STAT3 stimulates the autocrine IL-6 loop, and IGF-IR activation induced by both IL-6 and IGF enhances EMT through induction of the STAT3/NANOG/Slug axis [21,22].…”

ALKBH5-mediated m6A demethylation of FOXM1 mRNA promotes progression of uveal melanoma

“…In addition, METTL3-provoked m 6 A methylation of ZMYM1 mRNA facilitated EMT and gastric cancer metastasis [ 19 ]. Some studies have demonstrated that EMT promotes the metastasis and aggression of UM [ 20 , 21 ]. However, the effect of m 6 A modifications on EMT in UM has yet to be explored.…”

LncRNA LINC00518 Acts as an Oncogene in Uveal Melanoma by Regulating an RNA-Based Network

“…On the contrary, functional assays aimed to investigate its implication in metastatic processes showed that LINC00518 expression increased not only after EMT-induction by IL6 and HGF treatment, but also after HIF1A activation by CoCl 2 treatment. It has been reported that IL6 and HGF trigger EMT in vitro [ 29 , 30 , 31 , 32 , 33 , 34 ], also in UM cells [ 35 , 36 ], while CoCl 2 provokes a hypoxia-like response through HIF1A activation [ 37 ], which represents one of the key events in the metastatic cascade [ 38 ]. Based on our results, IL6 seems to be more efficient in EMT induction in UM cells compared to HGF, as confirmed by the higher increase in EMT markers.…”