Molecular Cancer：Circular RNA MAPK4 (circ-MAPK4) inhibits cell apoptosis via MAPKsignaling pathway by sponging miR-125a-3p in gliomas
On January 28, 2020, the team of Jiehua He and Liu Anmin from our hospital published an online publication entitled "Circular RNA MAPK4 (circ-MAPK4) inhibits cell apoptosis via MAPKsignaling pathway by sponging miR-125a-3p in gliomas" . Professor Liu Anmin and Professor Yin Dong of our school are the corresponding authors of the study.
Glioma is the most common and most aggressive primary malignant tumor in the central nervous system (CNS). There are still many unsolved mysteries about the role of circular RNA . In this study, the researchers first used bioinformatics methods to compare retinoic acid-stimulated mouse P19 embryonic cancer cells on day 0 and day 4 to obtain a large number of differential circRNAs, and screened and identified circ-MAPK4 (has_circ_0047688), which is significantly down-regulated in the early neural differentiation process.
Researchers confirmed that circ-MAPK4 is highly expressed in glioma tissue: Compared with normal brain tissue, circ-MAPK4 is significantly higher in glioma tissue, and is positively correlated with tumor staging. At the same time, there is no difference in the expression of MAPK4 mRNA in glioma and normal brain tissue.
Cell experiments show that circ-MAPK4 acts as an oncogene: circ-MAPK4 has high expression levels in the glioma cell lines U138 and U373;Knockout circ-MAPK4 in the cell lines mediated by si-RNA significantly inhibits cell proliferation, clone formation and invasion, and promotes cell apoptosis. In addition, animal experiments show that circ-MAPK4 promotes tumorigenesis and development: Stable knockout of circ-MAPK4 in mouse gliomas in situ resulted in slower growth and volume reduction of gliomas subcutaneously and in situ, which ultimately prolonged the survival time of tumor mice.
The study also found that miR-125a-3p can be used as the target of circ-MAPK4: the use of target prediction, pull down experiment and the expression level of each miRNA in tumor tissue samples jointly verified that miR-125a-3p is circ-MAPK4 potential target; The expression of miR-125a-3p and circ-MAPK4 in glioma tissues is correlated. Further experiments confirmed that miR-125a-3p inhibitors can block cells caused by knocking out circ-MAPK4 effect.
Further mechanism research found that the effect of circ-MAPK4 depends on the p38/MAPK pathway: Western blotting proved that knockout circ-MAPK4 showed higher levels of p38/MAPK phosphorylation, and p38/MAPK phosphorylation inhibitors that can rescue the changes caused by circ-MAPK4 knockout.
In glioma, circ-MAPK4, as an oncogene, is reversed up-regulated and is related to the clinicopathological stage of glioma. In vivo and in vitro experiments have confirmed that circ-MAPK4 can promote glioma cells survival. In addition, the researchers also proved that circ-MAPK4 is involved in regulating the p38/MAPK pathway, thereby affecting the proliferation and apoptosis of glioma. miR-125a-3p (a miRNA) shows tumor suppressor function by weakening the p38/MAPK pathway, and this inhibitory effect can be enhanced by inhibiting circ-MAPK4. Inhibition of miR-125a-3p can partially rescue the increase in p38/MAPK phosphorylation and rescue the apoptosis induced by circ-MAPK4 knockdown. Research conclusions show that: circ-MAPK4 plays a key role in the survival and apoptosis of glioma cells by regulating the p38/MAPK signaling pathway by sponging miR-125a-3p, which can provide a new idea for the treatment of glioma.
Article Link: https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-019-1120-1