Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Sci Rep. 2020 Mar 5;10(1):4155. doi: 10.1038/s41598-020-60218-9.
Malignant gliomas are the most common tumor in central nervous system with poor prognosis. Due to the limitation of histological classification in earlier diagnosis and individualized medicine, it is necessary to combine the molecular signatures and the pathological characteristics of gliomas. Lots of microRNAs presented abnormal expression in gliomas and modulated gliomas development. Exploration the miRNAs profile is helpful for the diagnosis, therapy and prognosis of gliomas. It has been demonstrated that miR-144 plays important roles in solid tumors. However, the detail mechanisms remained unrevealed. In this study, we have demonstrated the level of miR-144 decreased in glioma tissues from patients, especially in gliomas with higher grades. MiR-144 was also validated have lower expression in glioma cell lines compared with cortical neuron cell by using qRT-PCR. The in vitro functional experiment indicated miR-144 improved gliomas progression through repressing proliferation, sensitizing to chemotherapeutics and inhibiting metastasis. We further identified fibroblast growth factor 7 (FGF7) and Caveolin 2 (CAV2) were target genes of miR-144 by luciferase reporter assay and western blotting. The mechanisms study suggested forced FGF7 expression elevated Akt activation and decreased reactive oxygen species (ROS) generation. The MTT and cell cycle assay indicated miR-144 suppressed glioma cells proliferation through modulating FGF mediated Akt signaling pathway. Meanwhile, miR-144 promoted Temozolomide (TMZ) induced apoptosis in glioma cells via increasing ROS production by using FACS. On the other hand, CAV2, as another target of miR-144, accelerated glioma cells migration and invasion via promoting glioma cells EMT progress. Retrieved expression of FGF7 or CAV2 rescued the proliferation and migration function mediated by miR-144. Furthermore, the in vivo experiments in PDX models displayed the anti-tumor function of miR-144, which could be retrieved by overexpression of FGF7 and CAV2. Taken together, these findings indicated miR-144 acted as a potential target against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new therapeutic strategy and prognostic indicator for gliomas.
恶性神经胶质瘤是中枢神经系统最常见的肿瘤，预后较差。由于在早期诊断和个体化医学中组织学分类的局限性，有必要结合神经胶质瘤的分子特征和病理特征。许多 microRNAs 在神经胶质瘤中呈现异常表达，并调节神经胶质瘤的发展。探索 microRNAs 谱有助于神经胶质瘤的诊断、治疗和预后。已经证明 miR-144 在实体瘤中发挥重要作用。然而，其详细机制仍未被揭示。在这项研究中，我们已经证明 miR-144 的水平在患者的神经胶质瘤组织中降低，特别是在分级较高的神经胶质瘤中。通过 qRT-PCR 也验证了 miR-144 在神经胶质瘤细胞系中的表达低于皮质神经元细胞。体外功能实验表明，miR-144 通过抑制增殖、增加化疗敏感性和抑制转移来改善神经胶质瘤的进展。我们进一步通过荧光素酶报告基因检测和 Western blot 验证了成纤维细胞生长因子 7 (FGF7) 和窖蛋白 2 (CAV2) 是 miR-144 的靶基因。机制研究表明，强制表达 FGF7 可激活 Akt 并减少活性氧 (ROS) 的产生。MTT 和细胞周期分析表明，miR-144 通过调节 FGF 介导的 Akt 信号通路抑制神经胶质瘤细胞的增殖。同时，miR-144 通过增加 ROS 的产生，促进 Temozolomide (TMZ) 诱导的神经胶质瘤细胞凋亡。另一方面，CAV2 作为 miR-144 的另一个靶基因，通过促进神经胶质瘤细胞 EMT 进展，加速神经胶质瘤细胞的迁移和侵袭。FGF7 或 CAV2 的表达恢复挽救了 miR-144 介导的增殖和迁移功能。此外，在 PDX 模型中的体内实验显示了 miR-144 的抗肿瘤作用，该作用可通过过表达 FGF7 和 CAV2 得到恢复。总之，这些发现表明 miR-144 可作为针对神经胶质瘤进展的潜在靶点，并揭示了一种新的调节机制，可为神经胶质瘤提供新的治疗策略和预后指标。
