Human glioblastoma (GBM) is the most aggressive malignancy of the CNS, with less than 5% survival. Despite great efforts to find effective therapeutics, current options remain very limited. To develop a targeted cancer therapeutic, we selected RNA aptamers against platelet-derived growth factor receptor α (PDGFRα), which is a receptor tyrosine kinase. One RNA aptamer (PDR3) with high affinity (0.25 nM) showed PDGFRα specificity and was internalized in U251-MG cells. Following treatment with the PDR3 aptamer, expression of the transcription factor STAT3 (signal transducer and activator of transcription 3) was inhibited, whereas the expression of the histone demethylase JMJD3 and the tumor suppressor p53 were upregulated. PDR3 also upregulated serine phosphorylation of p53, which subsequently mediated apoptosis through the death receptors: tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptors 1/2 (TRAIL-R1/R2), Fas-associated via death domain (FADD), and Fas. PDR3 significantly decreased cell viability in a dose-dependent manner. Furthermore, translocation of PDR3 into the nucleus induced hypomethylation at the promoters of cyclin D2. To assess the feasibility of targeted delivery, we conjugated PDR3 aptamer with STAT3-siRNA for a chimera. The PDR3-siSTAT3 chimera successfully inhibited the expression of target genes and showed significant inhibition of cell viability. In summary, our results show that well-tailored RNA aptamers targeting the PDGFRα-STAT3 axis have the potential to act as anti-cancer therapeutics in GBM.

人胶质母细胞瘤（GBM）是中枢神经系统中最具侵袭性的恶性肿瘤，生存率不到5％。尽管为寻找有效的疗法付出了巨大的努力，但是当前的选择仍然非常有限。为了开发有针对性的癌症治疗药物，我们选择了针对血小板衍生的生长因子受体α（PDGFRα）的RNA适体，PDGFRα是一种受体酪氨酸激酶。一种具有高亲和力（0.25 nM）的RNA适体（PDR3）显示出PDGFRα特异性，并被内化在U251-MG细胞中。用PDR3适体处理后，转录因子STAT3（信号转导子和转录激活子3）的表达受到抑制，而组蛋白脱甲基酶JMJD3和肿瘤抑制因子p53的表达上调。PDR3还上调了p53的丝氨酸磷酸化，随后通过死亡受体介导了细胞凋亡：肿瘤坏死因子（TNF）相关的凋亡诱导配体受体1/2（TRAIL-R1 / R2），通过死亡域（FADD）关联的Fas和Fas。PDR3以剂量依赖性方式显着降低细胞活力。此外，在细胞周期蛋白D2的启动子上，PDR3易位进入核诱导了甲基化不足。为了评估靶向递送的可行性，我们将PDR3适体与STAT3-siRNA结合用于嵌合体。PDR3-siSTAT3嵌合体成功抑制靶基因的表达，并显示出明显的细胞活力抑制作用。总之，我们的结果表明，针对PDGFRα-STAT3轴的量身定制的RNA适体具有在GBM中作为抗癌治疗剂的潜力。PDR3以剂量依赖性方式显着降低细胞活力。此外，在细胞周期蛋白D2的启动子上，PDR3易位进入核诱导了甲基化不足。为了评估靶向递送的可行性，我们将PDR3适体与STAT3-siRNA结合用于嵌合体。PDR3-siSTAT3嵌合体成功抑制靶基因的表达，并显示出明显的细胞活力抑制作用。总之，我们的结果表明，靶向PDGFRα-STAT3轴的量身定制的RNA适体具有在GBM中作为抗癌治疗剂的潜力。PDR3以剂量依赖性方式显着降低细胞活力。此外，在细胞周期蛋白D2的启动子上，PDR3易位进入核诱导了甲基化不足。为了评估靶向递送的可行性，我们将PDR3适体与STAT3-siRNA结合用于嵌合体。PDR3-siSTAT3嵌合体成功抑制靶基因的表达，并显示出明显的细胞活力抑制作用。总之，我们的结果表明，针对PDGFRα-STAT3轴的量身定制的RNA适体具有在GBM中作为抗癌治疗剂的潜力。PDR3-siSTAT3嵌合体成功抑制靶基因的表达，并显示出明显的细胞活力抑制作用。总之，我们的结果表明，针对PDGFRα-STAT3轴的量身定制的RNA适体具有在GBM中作为抗癌治疗剂的潜力。PDR3-siSTAT3嵌合体成功抑制靶基因的表达，并显示出明显的细胞活力抑制作用。总之，我们的结果表明，针对PDGFRα-STAT3轴的量身定制的RNA适体具有在GBM中作为抗癌治疗剂的潜力。