EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis

Abstract

BackgroundCircular RNAs (circRNAs) have been found to play critical roles in the development and progression of various cancers. However, little is known about the effects of the circular RNA network on glioblastoma multiforme (GBM).MethodsA microarray was used to screen circRNA expression in GBM. Quantitative real-time PCR was used to detect the expression of circMMP9. GBM cells were transfected with a circMMP9 overexpression vector or siRNA, and cell proliferation, migration and invasion, as well as tumorigenesis in nude mice, were assessed to examine the effect of circMMP9 in GBM. Biotin-coupled miRNA capture, fluorescence in situ hybridization and luciferase reporter assays were conducted to confirm the relationship between circMMP9 and miR-124.ResultsIn this study, we screened differentially expressed circRNAs and identified circMMP9 in GBM. We found that circMMP9 acted as an oncogene, was upregulated in GBM and promoted the proliferation, migration and invasion abilities of GBM cells. Next, we verified that circMMP9 served as a sponge that directly targeted miR-124; circMMP9 accelerated GBM cell proliferation, migration and invasion by targeting miR-124. Furthermore, we found that cyclin-dependent kinase 4 (CDK4) and aurora kinase A (AURKA) were involved in circMMP9/miR-124 axis-induced GBM tumorigenesis. Finally, we found that eukaryotic initiation factor 4A3 (eIF4A3), which binds to the MMP9 mRNA transcript, induced circMMP9 cyclization and increased circMMP9 expression in GBM.ConclusionsOur findings indicate that eIF4A3-induced circMMP9 is an important underlying mechanism in GBM cell proliferation, invasion and metastasis through modulation of the miR-124 signaling pathway, which could provide pivotal potential therapeutic targets for the treatment of GBM.Graphical abstract Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0911-0) contains supplementary material, which is available to authorized users.

MicroRNA‐124: An emerging therapeutic target in cancer

“…Moreover, the binding of miR‐124‐3p to the 3'‐UTR of STAT3 inhibited the protein expression of STAT3 in glioblastoma cell lines (U87 and U251), indicating another therapeutic target for glioblastoma patients . Wang et al found that the circular RNA MMP9 (circMMP9) gene could sponge miR‐124, which is a novel underlying mechanism in glioblastoma cells (U87 and U251), regulating glioblastoma multiforme cell tumorigenesis through the circMMP9/miR‐124‐CDK4/AURKA signaling axis . Luo et al found that miR‐124‐3p could decrease Fra‐2 mRNA levels by a dual‐luciferase reporter assay, and increasing miR‐124‐3p in glioma cells could prevent classic cancer biological behaviors .…”

“…Prostate cancer (PC) is a common malignant tumor in older men and is one of the most fatal human cancers due to its insidious onset and the current lack of robust early diagnostic tests. miR‐124 is an independent prognostic marker for PC . The androgen receptor (AR) is known to have a strong association with the initiation and progression of PC.…”

“…86,87 Wang et al found that the circular RNA MMP9 (circMMP9) gene could sponge miR-124, which is a novel underlying mechanism in glioblastoma cells (U87 and U251), regulating glioblastoma multiforme cell tumorigenesis through the circMMP9/miR-124-CDK4/AURKA signaling axis. 88 Luo et al found that miR-124-3p could decrease Fra-2 mRNA levels by a dual-luciferase reporter assay, and increasing miR-124-3p in glioma cells could prevent classic cancer biological behaviors. 89 Moreover, Wu et al validated that miR-124-3p could inhibit EphA2 expression and its downstream pathway to regulate the growth and invasion of glioma cells (U87MG and LN229).…”

Overexpression of circ_0005198 sponges miR‐1294 to regulate cell proliferation, apoptosis, migration, and invasion in glioma

“…A recent report revealed that decreased miR‐1294 predicts an unfavorable prognosis for gastric cancer patients . In addition, miR‐1294 could inhibit oral squamous cell carcinoma proliferation via regulating c‐Myc expression . Chen et al documented miR‐1294 could inhibit cell growth and enhance the chemosensitivity of GM to temozolomide via direct targeting TPX2.…”

Overexpression of circular RNA circ‐CDC45 facilitates glioma cell progression by sponging miR‐516b and miR‐527 and predicts an adverse prognosis

“…[10][11][12] Emerging studies suggest that miRNA is included in tumorigenesis. 16 The spliced length of circ-CDC45 is 385 bp and it has not been studied before. 13 circRNA could function as a competing endogenous RNA (ceRNA) that competes for miRNA binding, and blocks miRNAs-mediated target gene silencing.…”