rRNA甲基转移酶NSUN5调控BMI1-DUSP4/ERK轴促进胶质母细胞瘤进展的机制研究

RNA甲基化失调在肿瘤发生发展中发挥重要作用。我们前期发现胶质母细胞瘤rRNA甲基转移酶NSUN5的高表达与患者不良预后密切相关，NSUN5敲低明显抑制肿瘤细胞增殖和肿瘤干细胞自我更新；组学分析显示NSUN5敲低影响原癌基因BMI1的翻译活性，导致ERK负向调控基因DUSP4的转录显著激活。因此我们提出假说：NSUN5敲低导致BMI1蛋白水平下降、DUSP4转录上调从而抑制ERK信号通路活化。本课题拟在细胞、动物水平检测NSUN5敲低、NSUN5敲低同时过表达BMI1对胶质母细胞瘤细胞增殖、凋亡、氧化应激、克隆形成能力和体内肿瘤进展的影响，同时分析比较DUSP4基因表达和ERK活性的差异；并利用临床样本分析NSUN5和BMI1蛋白水平、ERK磷酸化水平之间的相关性，以及与患者预后之间的关系，从而建立NSUN5-BMI1-DUSP4/ERK的轴向调控机制，为建立新的靶向治疗策略提供理论依据。

Aberrant RNA methylation plays an important role in tumorigenesis and development. We previously demonstrated that high expression of the rRNA methyltransferase NSUN5 in glioblastoma was closely related to a poor prognosis of patients. NSUN5 knockdown significantly inhibited the proliferation of tumor cells and self-renewal of tumor stem cells; omics analysis showed that NSUN5 knockdown affected the translation activity of proto-oncogene BMI1, leading to significant activation of the transcription of the DUSP4 gene linked to negative regulation of ERK. Therefore, we hypothesized that NSUN5 knockdown led to a decrease in BMI1 protein levels and upregulation of DUSP4 transcription, thereby inhibiting the activation of the ERK signaling pathway. The aim of this study was to detect the effects of NSUN5 knockdown and BMI1 overexpression on proliferation, apoptosis, oxidative stress, colony formation ability, and tumor progression in glioblastoma cells in vivo and in vitro. We also aimed to compare the differences in DUSP4 gene expression and ERK activity, to analyze the correlations between NSUN5 and BMI1 protein levels and ERK phosphorylation levels in clinical samples, and to analyze the prognosis of patients. The mechanism of the regulation of the NSUN5-BMI1- DUSP4/ERK axis was demonstrated to provide a theoretical basis for the development of new targeted treatment strategies.