IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines

Abstract

Interleukin-6 (IL-6) is a growth and survival factor in human glioblastoma cells and plays an important role in malignant progression. However, its role in glioblastoma invasion is still unknown. This study shows how IL-6 promotes cell invasion and migration in U251 and T98G glioblastoma cell lines. The underlying mechanism includes both protease-dependent and -independent manners. Stimulation with IL-6 increased MMP9 expression in the two cell lines but had no influence on MMP2 expression. Fascin-1 is a cell skeleton binding protein and plays a key role in cell migration and invasion. Its binding style directly influences cell morphology and tendency to become deformed. After IL-6 exposure, fascin-1 expression increased in an IL-6 dose-dependent manner. Immunofluorescence also revealed that the binding style of fascin-1 had changed after IL-6 exposure, resulting in a more invasive phenotype of the cells. Three most commonly emphasized invasion-associated signaling pathways, including JAK-STAT3, p42/44 MAPK, and PI3K/AKT, were verified to further illustrate its underlying mechanism. Only phosphorylation of STAT3 at ser 727 site paralleled the IL-6 stimulation, and JSI-124, a specific JAK-STAT3 pathway blocker, deterred the invasion and migration promotive effect of IL-6, indicating that the JAK/STAT3 pathway mediates signal transduction. Furthermore, IL-6 also acts in a paracrine fashion to promote vascular endothelial cell migration, thus facilitating tumor angiogenesis and invasion. These results suggest that IL-6 promotes glioblastoma cell invasion and angiogenesis and may be a potential anti-invasion target.

Signal Transducers and Activators of Transcription 3 (STAT3) Directly Regulates Cytokine-induced Fascin Expression and Is Required for Breast Cancer Cell Migration

“…Fascin levels can be abnormally high in many cancers (18 -20), and this work shows that IL-6 or OSM treatment can further increase these levels to promote cell migration (21). It is also possible that other factors, such as ␤-catenin and cAMPresponse element-binding protein, contribute to the expression of fascin in cancer cells (30 -32).…”

“…However, it is not known how fascin expression is elevated in metastatic tumor cells. It has been reported that IL-6 increases the expression of fascin in glioblastoma cells to promote cell invasion (21). This observation suggests a correlation between STAT3 activation and an increase in fascin expression.…”

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

“…Furthermore, we found IL-6 and ICAM1, which are upregulated only in high-risk tumors, as the key mediators of chemosensitivity. In good correlation, IL-6 and ICAM1 were found associated with invasion, angiogenesis, tumor growth, chemoresistance, and prognosis in many cancers (29)(30)(31)(32). .…”

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

“…1E). We also investigated the expression of several cytokines, which are previously reported to promote invasion or angiogenesis in glioma (36,37). The expression of IL-2, IL-6, and IL-10 were upregulated in U87R cells compared with U87 cells (Fig.…”