Purpose

Glioma is the most common cancer in the central nervous system and has a high mortality rate. Despite advances that have been made in the treatment of glioma, its prognosis still remains poor. Dysregulation of miRNAs has been reported in many cancers, including glioma. Here, we set out to assess the role of miR-650 in glioma, including its diagnostic and therapeutic potential.

Methods

miR-650 and RAS-like estrogen-regulated growth inhibitor (RERG) expression levels were analyzed using qRT-PCR in primary glioma tissues and cell lines. Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine, colony formation, Western blotting, scratch wound healing, Transwell, adhesion, autophagy, immunofluorescence, luciferase reporter, electrophoretic mobility shift, tumor xenograft and flow cytometry assays were employed to investigate the mechanisms underlying the effect of miR-650 and RERG on glioma development.

Results

miR-650 was found to be up-regulated in glioma tissues and cell lines compared to non-cancerous brain tissues and neural progenitor cells, respectively. We also found that miR-650 promoted cell proliferation, migration and invasion in glioma cells, and enhanced glioma tumor formation and growth in vivo. We identified and validated RERG as a direct target of miR-650. RERG was shown to act as a tumor suppressor in glioma cells, and its suppressor roles were rescued by miR-650. We found that nuclear factor (NF)-κB bound to the promoter of miR-650 and enhanced its expression. PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2), as a co-factor of the RERG/PHLPP2 complex, mediated miR-650-induced activation of the protein kinase B/extracellular-signal-regulated kinase/NF-κB signaling pathways.

Conclusions

Our data revealed novel functional roles for miR-650 in glioma development and may provide new avenues for future clinical applications.

中文翻译：

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NF-κB 介导的 miR-650 通过靶向神经胶质瘤细胞中的 RERG 发挥致癌作用并激活 AKT/ERK/NF-κB 通路。

目的

胶质瘤是中枢神经系统中最常见的癌症，死亡率很高。尽管神经胶质瘤的治疗取得了进展，但其预后仍然很差。在许多癌症中已经报道了 miRNA 的失调，包括神经胶质瘤。在这里，我们着手评估 miR-650 在神经胶质瘤中的作用，包括其诊断和治疗潜力。

方法

使用 qRT-PCR 在原代胶质瘤组织和细胞系中分析 miR-650 和 RAS 样雌激素调节生长抑制剂 (RERG) 的表达水平。细胞计数试剂盒 8、5-乙炔基-2'-脱氧尿苷、集落形成、蛋白质印迹、划痕伤口愈合、Transwell、粘附、自噬、免疫荧光、荧光素酶报告基因、电泳迁移率变化、肿瘤异种移植和流式细胞术检测miR-650 和 RERG 对胶质瘤发展影响的潜在机制。

结果

与非癌性脑组织和神经祖细胞相比，发现 miR-650 在神经胶质瘤组织和细胞系中分别上调。我们还发现 miR-650 促进了胶质瘤细胞的增殖、迁移和侵袭，并增强了体内胶质瘤的形成和生长。我们确定并验证了 RERG 作为 miR-650 的直接靶标。RERG 被证明在神经胶质瘤细胞中充当肿瘤抑制因子，并且其抑制作用被 miR-650 拯救。我们发现核因子 (NF)-κB 与 miR-650 的启动子结合并增强其表达。PH 结构域和富含亮氨酸的重复蛋白磷酸酶 2 (PHLPP2)，作为 RERG/PHLPP2 复合物的辅助因子，介导 miR-650 诱导的蛋白激酶 B/细胞外信号调节激酶/NF-κB 信号通路的激活.

结论

我们的数据揭示了 miR-650 在胶质瘤发展中的新功能作用，并可能为未来的临床应用提供新的途径。