Rationale: The malignant phenotypes of glioblastomas (GBMs) are primarily attributed to glioma stem cells (GSCs). Our previous study and other reports have suggested that both miR-139 and its host gene PDE2A are putative antitumor genes in various cancers. The aim of this study was to investigate the roles and mechanisms of miR-139/PDE2A in GSC modulation./nMethods: Clinical samples were used to determine miR-139/PDE2A expression. Patient-derived glioma stem-like cells (PD-GSCs) were stimulated for immunofluorescent staining, sphere formation assays and orthotopic GBM xenograft models. Bioinformatic analysis and further in vitro experiments demonstrated the downstream molecular mechanisms of miR-139 and PDE2A. OX26/CTX-conjugated PEGylated liposome (OCP) was constructed to deliver miR-139 or PDE2A into glioma tissue specifically./nResults: We demonstrated that miR-139 was concomitantly transcribed with its host gene PDE2A. Both PDE2A and miR-139 indicated better prognosis of gliomas and were inversely correlated with GSC stemness. PDE2A or miR-139 overexpression suppressed the stemness of PD-GSCs. FZD3 and β-catenin, which induced Wnt/β-catenin signaling activation, were identified as targets of miR-139 and mediated the effects of miR-139 on GSCs. Meanwhile, PDE2A suppressed Wnt/β-catenin signaling by inhibiting cAMP accumulation and GSK-3β phosphorylation, thereby modulating the self-renewal of PD-GSCs. Notably, Notch1, which is also a target of miR-139, suppressed PDE2A/miR-139 expression directly via downstream Hes1, indicating that miR-139 promoted its own expression by the miR-139-Notch1/Hes1 feedback circuit. Expectedly, targeted overexpression miR-139 or PDE2A in glioma with OCP system significantly repressed the stemness and decelerated glioma progression./nConclusions: Our findings elaborate on the inhibitory functions of PDE2A and miR-139 on GSC stemness and tumorigenesis, which may provide new prognostic markers and therapeutic targets for GBMs.

中文翻译：

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miR-139/PDE2A-Notch1 反馈电路通过抑制 Wnt/β-catenin 信号传导来抑制胶质瘤的干性

理由：胶质母细胞瘤 (GBM) 的恶性表型主要归因于胶质瘤干细胞 (GSC)。我们之前的研究和其他报告表明，miR-139 及其宿主基因 PDE2A 都是各种癌症中推定的抗肿瘤基因。本研究的目的是研究 miR-139/PDE2A 在 GSC 调节中的作用和机制。/n方法：临床样本用于确定 miR-139/PDE2A 的表达。刺激患者来源的胶质瘤干细胞样细胞 (PD-GSC) 进行免疫荧光染色、球体形成测定和原位 GBM 异种移植模型。生物信息学分析和进一步的体外实验证明了 miR-139 和 PDE2A 的下游分子机制。OX26/CTX 缀合的 PEG 化脂质体 (OCP) 被构建用于将 miR-139 或 PDE2A 特异性递送到胶质瘤组织中。/n结果：我们证明了miR-139与其宿主基因PDE2A同时转录。PDE2A 和 miR-139 均表明胶质瘤预后较好，并且与 GSC 干性呈负相关。PDE2A 或 miR-139 过表达抑制了 PD-GSCs 的干性。诱导 Wnt/β-catenin 信号激活的 FZD3 和 β-catenin 被确定为 miR-139 的靶标，并介导 miR-139 对 GSCs 的影响。同时，PDE2A 通过抑制 cAMP 积累和 GSK-3β 磷酸化来抑制 Wnt/β-catenin 信号，从而调节 PD-GSCs 的自我更新。值得注意的是，同样是 miR-139 的靶标的 Notch1 直接通过下游 Hes1 抑制 PDE2A/miR-139 的表达，表明 miR-139 通过 miR-139-Notch1/Hes1 反馈回路促进其自身的表达。预计，结论：我们的研究结果详细阐述了 PDE2A 和 miR-139 对 GSC 干性和肿瘤发生的抑制作用，这可能为 GBMs 提供新的预后标志物和治疗靶点。