Circular RNA MAPK4 (circ-MAPK4) inhibits cell apoptosis via MAPK signaling pathway by sponging miR-125a-3p in gliomas
Circular RNA MAPK4 (circ-MAPK4) inhibits cell apoptosis via MAPK signaling pathway by sponging miR-125a-3p in gliomas
复制标题
环状 RNA MAPK4 (circ-MAPK4) 通过 MAPK 信号通路通过海绵状胶质瘤中的 miR-125a-3p 抑制细胞凋亡
DOI：
10.1186/s12943-019-1120-1
复制
发表时间：
2020-01-28
期刊：
影响因子：
37.3
通讯作者：
Liu, Anmin
中科院分区：
文献类型：
--
作者：
He, Jiehua;Huang, Zuoyu;Liu, Anmin
研究背景近年来的研究表明，环状RNA（circular RNA，circRNA）在多种肿瘤中发挥着重要作用，并经常发生调控异常。神经胶质瘤是中枢神经系统（CNS）中最常见、最具侵袭性的原发性恶性肿瘤，circRNA在CNS中含量丰富，但对其临床意义和作用的研究较少。实时荧光定量PCR检测circ-MAPK 4和靶miRNAs的表达。将circ-MAPK 4 siRNA转染胶质瘤细胞，通过体外和体内细胞增殖、凋亡、transwell实验、肿瘤发生和TUNEL实验检测circ-MAPK 4对胶质瘤细胞的影响。结果在本研究中，我们发现了一种在神经细胞分化早期表达下调的circRNA，即circ-MAPK 4（has_circ_0047688）。在胶质瘤中，circ-MAPK 4作为癌基因，呈负性上调，并与胶质瘤的临床病理分期相关（P< 0.05）。接下来，我们验证了circ-MAPK 4在体外和体内促进胶质瘤细胞的存活并抑制其凋亡。进一步证实circ-MAPK 4参与调控p38/MAPK信号通路，从而影响胶质瘤的增殖和凋亡。miR-125 a-3 p通过抑制p38/MAPK通路发挥抑瘤作用，抑制circ-MAPK 4可使p38/MAPK通路增强，而circ-MAPK 4可使p38/MAPK通路减弱。miR-125 a-3 p的抑制可部分缓解p38/MAPK磷酸化水平的升高和circ-MAPK 4敲低诱导的凋亡量的增加。结论circ-MAPK 4通过miR-125 a-3 p的调节，通过p38/MAPK信号通路参与胶质瘤细胞的存活和凋亡，可能成为胶质瘤治疗的新靶点。
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 vitroand 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 vitroandin 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.