Turkish Neurosurgery
Inhibition of the invasion of human glioblastoma U87 cell line by ruxolitinib: a molecular player of miR-17 and miR-20a regulating JAK/STAT pathway
emre delen1, oguzhan doganlar2, zeynep banu doganlar2, ozlem delen3
1University of Trakya School of Medicine, Neurosurgery Department, Edirne,
2University of Trakya School of Medicine, Medical Biology Department , Edirne,
3University of Trakya School of Medicine, Histology and Embryology Department, Edirne,
DOI: 10.5137/1019-5149.JTN.26122-19.1
Aim:We aimed to determine the interaction between ruxolitinib, JAK/STAT signalling, and two angioMiRs to expose potential target molecules in the inhibition of glioblastoma invasion.Material and Methods:The invasion properties of glioblastoma were analyzed using a cancer cell spheroid invasion assay. Following treatment of 195 nM ruxolitinib, the relative expression levels of miR-17 and miR-20a and genes of IL-6/JAK/STAT3 receptor signaling belonging to the JAK/STAT pathway were measured by qRT-PCR in treated and untreated three-dimensional tumor spheres of U87 cells. Results:Our results indicated that a therapeutic dose of ruxolitinib (195 nM) significantly increased miR-17 and miR-20a expression. Ruxolitinib treatment resulted in the production of IL-6 and active formation of IL-6 receptor complex for the subsequent activation of the IL-6R/JAK2/STAT3 axis. However, ruxolitinib treatment significantly decreased the expression of JAK2 and PI3K. Person correlation analyses revealed a strong negative correlation of miR-17 with JAK2, STAT3, and PI3K expressions, and also miR-20a has a negative correlation with expression levels of JAK2 and PI3K. The only positive correlation was found to be between miR-20a and IL-6, gp130 expressions.Conclusion:The specific JAK2 inhibitor ruxolitinib plays an important role in glioblastoma angiogenesis biology via inhibiting IL-6 receptor-dependent JAK/STAT signaling. Additionally, both miR-17a-3p and miR-20a overexpression induced by ruxolitinib treatment may be playing a major role in downregulated JAK2, STAT3, and PI3K proteins. Our results suggest that miR-17-3p and miR-20a-5p may serve as new therapeutic targets for the treatment of glioblastoma.
Corresponding author : emre delen