Interferon Regulatory Factor 7 Promoted Glioblastoma Progression and Stemness by Modulating IL-6 Expression in Microglia

Abstract

Background: Interferon Regulatory Factor 7 (IRF7) is associated with chronic inflammation initiated by the activation of microglia. However it remains poorly defined how IRF7 activates microglia to initiate inflammatory microenvironment, and thus promotes the growth and malignancy of glioblastoma multiforme (GBM). This study investigated the role of IRF7 expression in microglia which increases GBM progression.

Methods: We established stable human microglia (HMs) over-expressing IRF-7 or empty vector by lentiviral transduction and stable selection. These HM-IRF-7 cells were co-cultured with U87-MG to examine their influence on GBM, in terms of cell proliferation, apoptosis and stemness of U87-MG. By qRT-PCR and ELISA assays, the expression of key genes and secretion of inflammatory factors were identified in inflammatory signal pathway respectively. We also analyzed whether the expression of IRF7 and its target gene IL-6 correlated with PFS (progression-free survival) and OS (overall survival) in clinical samples by Kaplan-Meier survival curves.

Results: HMs can be engineered to stably express high level of IFR7 with IRF7 lentivirus, and was found to promote U87-MG growth and inhibit its apoptosis in co-culture. Meanwhile, U87-MG seemed to show stem cell character with ALDH1 expression. These results may be related to IRF7 initiating IL-6 expression and secretion in both HM and U87-MG cells. The IRF7 and IL-6 were highly expressed in GBM tissues, and IL-6 secretion was high in GBM serums, both of which were significantly correlated with PFS and OS.

Conclusions: The immune function of HMs was changed while it expressed IRF7 genes. The results demonstrated for the first time that IRF7 of microglia promoted GBM growth and stemness by mediating IL-6 expression, and revealed that IRF-7 and IL-6 were independent factors affecting the overall survival probability.