MicroRNA-93 acts as an "anti-inflammatory tumor suppressor" in glioblastoma. Issue 1 (18th April 2020)

• Record Type: Journal Article
• Authors: Hübner, Max; Moellhoff, Nicholas; Effinger, David; Hinske, Christian Ludwig; Hirschberger, Simon; Wu, Tingting; Müller, Martin Bernhard; Strauß, Gabriele; Kreth, Friedrich-Wilhelm; Kreth, Simone
• Is Part Of: Neuro-oncology advances. Volume 2:Issue 1(2020)
• Publication Date: 2020-04-18
• Subjects: 616.99481
• DOI: 10.1093/noajnl/vdaa047
• Languages: English
• ISSNs: 2632-2498

Abstract

Abstract: Background: Inflammation is an important driver of malignant glioma disease. Inflammatory mediators are not only produced by immune cells in the tumor microenvironment, but also by glioblastoma (GBM) cells themselves creating a mutually reinforcing loop. We here aimed at identifying an "anti-inflammatory switch" that allows to dampen inflammation in GBM. Methods: We used human GBM specimens, primary cultures, and cell lines. The response of GBM cells toward inflammatory stimuli was tested by incubation with supernatant of stimulated human immune cells. Expression levels were measured by whole transcriptome microarrays and qRT-PCR, and protein was quantified by LUMINEX and SDS-PAGE. MicroRNA binding to 3′UTRs was analyzed by luciferase assays. Proliferation rates were determined by flow cytometry, and invasion and angiogenesis were studied using migration and endothelial tube formation assays. Results: We demonstrated GBM cells to secrete high amounts of proinflammatory mediators in an inflammatory microenvironment. We found miR-93 as a potential "anti-inflammatory tumor suppressor" dramatically downregulated in GBM. Concordantly, cytokine secretion dropped after miR-93 re-expression. Transfection of miR-93 in GBM cells led to down-regulation of hubs of the inflammatory networks, namely, HIF-1α and MAP3K2 as well as IL-6, G-CSF, IL-8, LIF, IL-1β, COX2, and CXCL5. We showed only COX2 and CXCL5 to be indirectly regulated by miR-93 while all other genes are true targets. Phenotypically, re-expression of miR-93 in GBM cells substantially suppressed proliferation, migration, and angiogenesis. Conclusions: Alleviating GBM-derived inflammation by re-expression of miR-93 may be a powerful tool to mitigate these tumors' aggressiveness and holds promise for new clinical approaches.