Recently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the effects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory effect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and finally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while offering a possible target for treating human glioma in the future.

中文翻译：

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miR-29a 通过调节 P53/MDM2 反馈回路使神经胶质瘤细胞对替莫唑胺的反应敏感

最近，miRNA在调节脑肿瘤中常见的致瘤过程和操纵信号通路中的关键功能已经得到认可。值得注意的是，miR-29a 与 p53 信号密切相关，有助于胶质瘤的发展。然而，miR-29a与p53信号相互作用的分子机制仍有待揭示。在此，共使用 30 个神经胶质瘤组织和 10 个非癌组织来研究 miR-29a 的表达。应用CCK-8测定和Transwell测定来鉴定miR-29a改变表达对体外胶质瘤细胞恶性生物学行为的影响，包括增殖、凋亡、迁移和侵袭。双荧光素酶报告基因检测用于进一步验证 p53 或 miR-29a 分别对 miR-29a 或 MDM2 的调节作用，在转录水平。结果表明，miR-29a的表达与人脑胶质瘤的肿瘤分级呈负相关；同时在体外抑制细胞增殖、迁移和侵袭，促进胶质瘤细胞凋亡。从机制上讲，p53 诱导 miR-29a 表达，导致 miR-29a 靶向的 MDM2 异常表达，最终使 p53-miR-29a-MDM2 反馈回路的活性失衡。此外，调节 p53/MDM2 信号的 miR-29a 使神经胶质瘤细胞对替莫唑胺治疗的反应敏感。总之，该研究证明了胶质瘤发生的潜在分子机制，同时为未来治疗人类胶质瘤提供了可能的靶点。同时在体外抑制细胞增殖、迁移和侵袭，促进胶质瘤细胞凋亡。从机制上讲，p53 诱导 miR-29a 表达，导致 miR-29a 靶向的 MDM2 异常表达，最终使 p53-miR-29a-MDM2 反馈回路的活性失衡。此外，调节 p53/MDM2 信号的 miR-29a 使神经胶质瘤细胞对替莫唑胺治疗的反应敏感。总之，该研究证明了胶质瘤发生的潜在分子机制，同时为未来治疗人类胶质瘤提供了可能的靶点。同时在体外抑制细胞增殖、迁移和侵袭，促进胶质瘤细胞凋亡。从机制上讲，p53 诱导 miR-29a 表达，导致 miR-29a 靶向的 MDM2 异常表达，最终使 p53-miR-29a-MDM2 反馈回路的活性失衡。此外，调节 p53/MDM2 信号的 miR-29a 使神经胶质瘤细胞对替莫唑胺治疗的反应敏感。总之，该研究证明了胶质瘤发生的潜在分子机制，同时为未来治疗人类胶质瘤提供了可能的靶点。最终使 p53-miR-29a-MDM2 反馈回路的活性失衡。此外，调节 p53/MDM2 信号的 miR-29a 使神经胶质瘤细胞对替莫唑胺治疗的反应敏感。总之，该研究证明了胶质瘤发生的潜在分子机制，同时为未来治疗人类胶质瘤提供了可能的靶点。最终使 p53-miR-29a-MDM2 反馈回路的活性失衡。此外，调节 p53/MDM2 信号的 miR-29a 使神经胶质瘤细胞对替莫唑胺治疗的反应敏感。总之，该研究证明了胶质瘤发生的潜在分子机制，同时为未来治疗人类胶质瘤提供了可能的靶点。