miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling.
miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling.
复制标题
miR-139/PDE2A-Notch1 反馈电路通过抑制 Wnt/β-连环蛋白信号传导来抑制神经胶质瘤的干性。
DOI：
10.7150/ijbs.62858
复制
发表时间：
2021
影响因子：
9.2
通讯作者：
Zhao JL
中科院分区：
文献类型：
--
作者：
Li SZ;Ren KX;Zhao J;Wu S;Li J;Zang J;Fei Z;Zhao JL
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 都是各种癌症中假定的抗肿瘤基因。本研究的目的是探讨 miR-139/PDE2A 在 GSC 调节中的作用和机制。方法：使用临床样本测定 miR-139/PDE2A 表达。刺激患者来源的胶质瘤干样细胞 (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 缀合的聚乙二醇化脂质体 (OCP) 被构建用于将 miR-139 或 PDE2A 特异性递送至神经胶质瘤组织中。结果：我们证明 miR-139 与其宿主基因 PDE2A 伴随转录。 PDE2A 和 miR-139 均表明神经胶质瘤的预后较好，并且与 GSC 干性呈负相关。 PDE2A 或 miR-139 过表达抑制了 PD-GSC 的干性。 FZD3 和 β-catenin 诱导 Wnt/β-catenin 信号传导激活，被确定为 miR-139 的靶标，并介导 miR-139 对 GSC 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信号传导，从而调节PD-GSC的自我更新。值得注意的是，Notch1（也是 miR-139 的靶标）直接通过下游 Hes1 抑制 PDE2A/miR-139 表达，表明 miR-139 通过 miR-139-Notch1/Hes1 反馈回路促进其自身表达。预期，使用 OCP 系统在神经胶质瘤中靶向过度表达 miR-139 或 PDE2A 可显着抑制干性并减缓神经胶质瘤进展。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功能，这可能为 GBM 提供新的预后标志物和治疗靶点。
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. Methods: 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. Results: 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. Conclusions: 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.
登录
查看更多内容
影响因子：
11
作者：
Delhaye S;Bardoni B
通讯作者：
Bardoni B
影响因子：
10.5
作者：
Rajakulendran, Nishani;Rowland, Katherine J.;Dirks, Peter B.
通讯作者：
Dirks, Peter B.
影响因子：
5.5
作者：
Li, Rui-Yan;Chen, Ling-Chao;Jiang, Chuan-Lu
通讯作者：
Jiang, Chuan-Lu
影响因子：
15.9
作者：
Daniel, Paul M.;Filiz, Gulay;Mantamadiotis, Theo
通讯作者：
Mantamadiotis, Theo
影响因子：
10.8
作者：
Gallego-Perez, Daniel;Chang, Lingqian;Shi, Junfeng;Ma, Junyu;Kim, Sung-Hak;Zhao, Xi;Malkoc, Veysi;Wang, Xinmei;Minata, Mutsuko;Kwak, Kwang J.;Wu, Yun;Lafyatis, Gregory P.;Lu, Wu;Hansford, Derek J.;Nakano, Ichiro;Lee, L. James
通讯作者：
Lee, L. James