EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway.

摘要: Sustaining a high growth rate requires tumors to exploit resources in their microenvironment. One example of this is the extensive angiogenesis that typical feature high-grade gliomas. Here, we show expression constitutively active mutant epidermal factor receptor, ΔEGFR (EGFRvIII, EGFR*, de2-7EGFR) associated with significantly higher levels pro-angiogenic interleukin (IL)-8 human glioma specimens and stem cells. Furthermore, ectopic different cell lines caused up 60-fold increases secretion IL-8. Xenografts these cells exhibit increased neovascularization, which not elicited by overexpressing wild-type (wt)EGFR or an additional kinase domain mutation. Analysis regulation IL-8 site-directed mutagenesis its promoter showed regulates through transcription factors nuclear (NF)-κB, activator protein 1 (AP-1) CCAAT/enhancer binding (C/EBP). Glioma constitutive activation DNA NF-κB, overexpression c-Jun upstream N-terminal (JNK) C/EBPβ. Selective pharmacological genetic targeting NF-κB AP-1 pathways efficiently blocked activity Moreover, RNA interference-mediated knock-down either subunit p65, ΔEGFR-expressing attenuated ability form induce when injected subcutaneously into nude mice. On contrary, lacking potently enhanced tumorigenicity produced highly vascularized tumors, suggesting importance cytokine regulators promoting tumor growth.