MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7
MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7
复制标题
MicroRNA-144 通过靶向 CAV2 和 FGF7 抑制神经胶质瘤进展并提高对替莫唑胺的敏感性。
DOI：
10.1038/s41598-020-60218-9
复制
发表时间：
2020-03-05
影响因子：
4.6
通讯作者：
Li, San-Zhong
中科院分区：
文献类型：
--
作者：
Liu, Zhi-Qin;Ren, Jing-Jing;Li, San-Zhong
恶性胶质瘤是中枢神经系统最常见的肿瘤，预后差。由于组织学分型在早期诊断和个体化治疗中的局限性，有必要将胶质瘤的分子生物学特征与病理学特征联合收割机结合起来。大量microRNA在胶质瘤中表达异常，调控胶质瘤的发生发展。探讨miRNAs的表达谱有助于胶质瘤的诊断、治疗和预后。研究表明，miR-144在实体瘤中发挥重要作用。然而，详细的机制仍然没有透露。在这项研究中，我们已经证明了miR-144在患者的胶质瘤组织中的水平降低，特别是在较高级别的胶质瘤中。通过使用qRT-PCR还验证了miR-144在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、对化疗药物增敏和抑制转移来改善胶质瘤的进展。通过荧光素酶报告基因分析和蛋白质印迹分析，我们进一步确定了成纤维细胞生长因子7（FGF 7）和小窝蛋白2（CAV 2）是miR-144的靶基因。机制研究表明，强制FGF 7表达增加Akt激活和减少活性氧（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信号通路抑制胶质瘤细胞增殖。同时，流式细胞仪检测miR-144通过增加ROS的产生促进TMZ诱导的胶质瘤细胞凋亡。另一方面，作为miR-144的另一个靶点，CAV 2通过促进胶质瘤细胞EMT进程来加速胶质瘤细胞的迁移和侵袭。FGF 7或CAV 2的恢复表达挽救了由miR-144介导的增殖和迁移功能。此外，PDX模型中的体内实验显示了miR-144的抗肿瘤功能，其可以通过FGF 7和CAV 2的过表达来恢复。综上所述，这些研究结果表明miR-144作为一个潜在的靶点，对胶质瘤的进展，并揭示了一个新的调控机制，这可能会提供一个新的治疗策略和胶质瘤的预后指标。
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.