Circular RNA MAPK4 (circ-MAPK4) inhibits cell apoptosis via MAPK signaling pathway by sponging miR-125a-3p in gliomas

Jiehua He,Anmin Liu,Shengwen Wang,Zuoyu Huang,H Phillip Koeffler,Lin Xie,Qianqian Zhang,Jianyou Liao,Dong Yin,Mingliang He,Leping Ouyang

doi:10.1186/s12943-019-1120-1

Abstract

BackgroundRecent evidences have shown that circular RNAs (circRNAs) are frequently dysregulated and play paramount roles in various cancers. circRNAs are abundant in central nervous system (CNS); however, few studies describe the clinical significance and role of circRNAs in gliomas, which is the most common and aggressive primary malignant tumor in the CNS.MethodsA bioinformatics analysis was performed to profile and screen the dyregulated circRNAs during early neural development. Quantitative real-time PCR was used to detect the expression of circ-MAPK4 and target miRNAs. Glioma cells were transfected with circ-MAPK4 siRNAs, then cell proliferation, apoptosis, transwell assays, as well as tumorigenesis and TUNEL assays, were performed to examine effect of circ-MAPK4 in vitro and vivo. Biotinylated-circ-MAPK4 probe based pull-down assay was conducted to confirm the relationship between circ-MAPK4 and miR-125-3p.ResultsIn this study, we identified a circRNA, circ-MAPK4 (has_circ_0047688), which was downregulated during early neural differentiation. In gliomas, circ-MAPK4 acted as an oncogene, was inversely upregulated and linked to clinical pathological stage of gliomas (P < 0.05). Next, we verified that circ-MAPK4 promoted the survival and inhibited the apoptosis of glioma cells in vitro and in vivo. Furthermore, we proved that circ-MAPK4 was involved in regulating p38/MAPK pathway, which affected glioma proliferation and apoptosis. Finally, miR-125a-3p, a miRNA exhibited tumor-suppressive function through impairing p38/MAPK pathway, which was increased by inhibiting circ-MAPK4 and could be pulled down by circ-MAPK4. Inhibition of miR-125a-3p could partly rescue the increased phosphorylation levels of p38/MAPK and the elevated amount of apoptosis inducing by knockdown of circ-MAPK4.ConclusionsOur findings suggest that circ-MAPK4 is a critical player in glioma cell survival and apoptosis via p38/MAPK signaling pathway through modulation of miR-125a-3p, which can serve as a new therapeutic target for treatment of gliomas.

Highlights

Recent evidences have shown that circular RNAs are frequently dysregulated and play paramount roles in various cancers. circRNAs are abundant in central nervous system (CNS); few studies describe the clinical significance and role of circRNAs in gliomas, which is the most common and aggressive primary malignant tumor in the CNS
(See figure on previous page.) Fig. 1 Characterization of circ-MAPK4 in human neural embryoid body and gliomas. (a) Heat map of microarray data which identified aberrantly expressed circRNAs in the first day (D0) and the 4th day (D4) upon inducing neural differentiation of murine P19 embryonic carcinoma (EC). (b) circ-MAPK4 is upregulated in glioma tissues compared with normal brain tissues (P < 0.05). (c) The level of MAPK4 mRNA did not show significant difference between glioma tissues and normal brain tissues (P > 0.05). (d) circ-MAPK4 is highly expressed in gliomas patients with advanced stages III + IV compared with I + II (P < 0.05). (e) Upper panel: Schematic representation of circ-MAPK4 formation
Circ-MAPK4 is highly expressed in early neural stage and glioma tissues, and data were correlated with clinic pathological parameters According to Rajewsky N.’s research of inducing mouse P19 embryonic carcinoma (EC) neural differentiation by stimulation with retinoic acid [18], a large amount of circRNAs were differentially expressed on the 4th day of induction which could be regarded as early neural differentiation

Summary

Introduction

Recent evidences have shown that circular RNAs (circRNAs) are frequently dysregulated and play paramount roles in various cancers. circRNAs are abundant in central nervous system (CNS); few studies describe the clinical significance and role of circRNAs in gliomas, which is the most common and aggressive primary malignant tumor in the CNS. CircRNAs are abundant in central nervous system (CNS); few studies describe the clinical significance and role of circRNAs in gliomas, which is the most common and aggressive primary malignant tumor in the CNS. Glioma is the most common and fatal primary nervous system tumor [1, 2], characterized by heterogeneous genetic molecular aberrations [3]. It can be sorted into four grades according to the WHO criteria 2007 [4], among which glioblastoma multiforme (GBM) belonging to WHO grade IV which is the most aggressive form with repeated recurrence. Elucidation of the molecular mechanisms underlying circRNAs may lead to promising therapeutic candidates; the mechanisms and functions of circRNAs are not completely clear in gliomas

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Conclusion