BACKGROUND 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); 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. METHODS A 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. RESULTS In 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. CONCLUSIONS Our 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.

中文翻译：

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环状RNA MAPK4（circ-MAPK4）通过使神经胶质瘤中的miR-125a-3p海绵化，通过MAPK信号通路抑制细胞凋亡。

背景技术最近的证据表明，环状RNA（circRNA）经常失调并且在各种癌症中起着至关重要的作用。circRNA在中枢神经系统（CNS）中丰富；但是，很少有研究描述circRNA在神经胶质瘤中的临床意义和作用，神经胶质瘤是CNS中最常见，最具侵略性的原发性恶性肿瘤。方法进行了生物信息学分析，以分析和筛选早期神经发育过程中表达异常的circRNA。实时定量PCR用于检测circ-MAPK4和靶标miRNA的表达。用circ-MAPK4 siRNA转染胶质瘤细胞，然后进行细胞增殖，凋亡，transwell分析以及肿瘤发生和TUNEL分析，以检测circ-MAPK4在体内和体外的作用。进行了基于生物素化的circ-MAPK4探针的下拉分析，以确认circ-MAPK4与miR-125-3p之间的关系。结果在这项研究中，我们鉴定了一个circRNA，circ-MAPK4（has_circ_0047688），在早期神经分化过程中被下调。在神经胶质瘤中，circ-MAPK4作为一种癌基因，被逆向上调，并与神经胶质瘤的临床病理阶段有关（P <0.05）。接下来，我们证实circ-MAPK4在体外和体内均可促进神经胶质瘤细胞的存活并抑制其凋亡。此外，我们证明circ-MAPK4参与调节p38 / MAPK通路，从而影响神经胶质瘤的增殖和凋亡。最后，miR-125a-3p（一种miRNA）通过削弱p38 / MAPK途径显示出肿瘤抑制功能，这种抑制作用通过抑制circ-MAPK4而增加，并可能被circ-MAPK4降低。抑制miR-125a-3p可以部分挽救p38 / MAPK磷酸化水平的提高和circ-MAPK4敲低诱导的凋亡增加。结论我们的研究结果表明，circ-MAPK4是通过调节miR-125a-3p通过p38 / MAPK信号通路在神经胶质瘤细胞存活和凋亡中发挥关键作用，可以作为治疗神经胶质瘤的新靶点。