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Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal
melanoma aggressiveness via epithelial-mesenchymal transition
#MMPMID29899166
Gong C
; Shen J
; Fang Z
; Qiao L
; Feng R
; Lin X
; Li S
Biosci Rep
2018[Aug]; 38
(4
): ? PMID29899166
show ga
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.
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