CS-26FIBULIN-3 REGULATES CANONICAL NFkB SIGNALING IN GLIOMA CELLS AND SURROUNDING STROMAL CELLS TO PROMOTE TUMOR INVASION.

摘要: Fibulin-3 (also known as EFEMP1) is an extracellular matrix protein secreted by glioma cells but absent from normal brain, which increases tumor invasion and resistance to apoptosis. activates the Notch pathway in its downstream mechanisms are unknown. Here we show that fibulin-3 canonical NFkB TNFα- Notch-dependent mechanisms, both surrounding brain. Moreover, demonstrate activation of necessary mediate pro-invasive effects glioma. Addition purified activated classical cascade (IKKa/b, IkBa, p65/RelA), increasing expression NFkB-regulated genes (MMP9, MMP13, TnC, MLCK, VEGF). Conversely, knockdown inhibited signaling, even presence TNFα, reduced NFkB-downstream genes. Further mechanistic analysis demonstrated TNFα convertase ADAM17 releases soluble activate signaling. At same time, downregulated deubiquitinase CYLD, regulated inhibits Soluble RelA/p65 not only also cultured astrocytes brain microvascular endothelial cells. quantitative immunohistochemistry increased phosphor-p65 GFAP-positive fibulin-3-overexpressing tumors compared control tumors. Inhibition pharmacologically with p65-specific siRNAs, significantly glioblastoma seeded slices. Taken together, our results suggest a novel major mechanism triggered their microenvironment, underlies role this ECM protein. Given specific tight hypothesize targeting may provide avenue for tumor-specific reduction signaling little collateral effect tissue.