Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
Department of Neurosurgery, The People's Hospital of Ningdu County, Ningdu, 342800, Jiangxi, China.
Biochem Biophys Res Commun. 2023 Sep 3;671:309-317. doi: 10.1016/j.bbrc.2023.05.057. Epub 2023 May 18.
Ferroptosis has excellent potential in glioblastoma (GBM) therapy. In this study, we attempted to explore the effect of miR 491-5p on ferroptosis in GBM.
In this study, publicly available ferroptosis-related genome maps were used to screen genes upregulated in GBM and their target genes. The Spearman correlation coefficient was applied to analyze the correlation between the tumor protein p53 gene (TP53) and miR-491-5p. The expressions of miR-491-5p and TP53 were determined. The protein abundances of the TP53-encoded factors p53 and p21 were measured. Cell proliferation, migration and invasion were assessed. We pretreated U251MG cells and GBM mice with a ferroptosis inducer (erastin). The mitochondrial state was observed. The contents of reactive oxygen species (ROS), total Fe and Fe were calculated.
The level of TP53 was significantly increased in GBM and negatively correlated with miR-491-5p. miR-491-5p overexpression promoted U251MG cell proliferation, migration and invasion and interfered with the p53/p21 pathway. TP53 supplement reversed the effects of miR-491-5p. U251MG cells and GBM mice exhibited significant accumulations of ROS and iron. Erastin promoted the expression of TP53. Inhibition of TP53 reversed erastin-induced physiological phenotypes. Moreover, miR-491-5p overexpression caused a decrease in the number of damaged mitochondria and the contents of ROS, total Fe and Fe. TP53 supplement disrupted miR-491-5p-repressed ferroptosis. Erastin could inhibit GBM growth, and miR-491-5p overexpression impeded the therapeutic effect of erastin.
Our findings reveal the functional diversity of miR-491-5p in GBM and suggest that miR-491-5p/TP53 signaling hinders the sensitivity of GBM to ferroptosis through the p53/p21 pathway.
铁死亡在胶质母细胞瘤（GBM）治疗中有很好的应用潜力。本研究旨在探索 miR 491-5p 对 GBM 中铁死亡的影响。
本研究利用公开的铁死亡相关基因组图谱筛选出在 GBM 中上调的基因及其靶基因。采用 Spearman 相关系数分析肿瘤蛋白 p53 基因（TP53）与 miR-491-5p 的相关性。检测 miR-491-5p 和 TP53 的表达水平，测量 TP53 编码因子 p53 和 p21 的蛋白丰度，评估细胞增殖、迁移和侵袭能力。用铁死亡诱导剂（erastin）预处理 U251MG 细胞和 GBM 小鼠，观察线粒体状态，计算活性氧（ROS）、总铁和铁含量。
TP53 在 GBM 中表达显著上调，与 miR-491-5p 呈负相关。miR-491-5p 过表达促进 U251MG 细胞增殖、迁移和侵袭，并干扰 p53/p21 通路。TP53 补充逆转了 miR-491-5p 的作用。U251MG 细胞和 GBM 小鼠中 ROS 和铁含量显著增加。erastin 促进了 TP53 的表达。抑制 TP53 逆转了 erastin 诱导的生理表型。此外，miR-491-5p 过表达导致受损线粒体数量减少和 ROS、总铁和铁含量降低。TP53 补充破坏了 miR-491-5p 抑制的铁死亡。erastin 可抑制 GBM 生长，而过表达 miR-491-5p 则阻碍了 erastin 的治疗效果。
本研究揭示了 miR-491-5p 在 GBM 中的功能多样性，并表明 miR-491-5p/TP53 信号通过 p53/p21 通路阻碍了 GBM 对铁死亡的敏感性。
