MicroRNA-451 Inhibits Migration of Glioblastoma while Making It More Susceptible to Conventional Therapy
MicroRNA-451 Inhibits Migration of Glioblastoma while Making It More Susceptible to Conventional Therapy
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DOI：
10.3390/ncrna5010025
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发表时间：
2019-03
期刊：
影响因子：
4.3
通讯作者：
D. Ogawa;Khairul Ansari;M. Nowicki;E. Salińska;Agnieszka Bronisz;J. Godlewski
中科院分区：
文献类型：
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作者：
D. Ogawa;Khairul Ansari;M. Nowicki;E. Salińska;Agnieszka Bronisz;J. Godlewski
恶性胶质母细胞瘤（GBM，胶质瘤）是最常见和侵袭性的原发性成人脑肿瘤。尽管进行了手术、放疗和化疗，但GBM患者的预后仍然很差。治疗成功的主要障碍是GBM细胞的侵袭性和治疗耐药性。侵袭性胶质瘤细胞离开原发肿瘤核心，向正常脑周围浸润，即使在手术切除、放化疗后也不可避免地复发。治疗耐药性允许在治疗时选择更具侵袭性和耐药性的亚群，包括GBM干细胞样细胞（GSCs），这是成功治疗的另一个严重障碍。通过对多个基因的调控，microrna可以协调复杂的基因表达程序，并作为细胞过程的主要调节剂。因此，基于microrna的治疗方法可以影响广泛的细胞程序，从而抑制侵袭和对放疗/化疗的敏感性。我们的数据表明，miR-451在体外减弱胶质瘤细胞的迁移和体内的侵袭。此外，我们发现miR-451使胶质瘤细胞对常规化疗和放疗敏感。我们的数据还表明，miR-451在体内受AMPK通路的调控，AMPK/miR-451环具有在胶质瘤细胞行为的增殖和迁移模式之间切换的能力。因此，我们假设AMPK/miR-451负互反馈回路允许GBM细胞/GSCs通过代谢和行为灵活性适应肿瘤“生态系统”，并且这种回路的破坏降低了侵袭性并减少了治疗耐药性。
Malignant glioblastoma (GBM, glioma) is the most common and aggressive primary adult brain tumor. The prognosis of GBM patients remains poor, despite surgery, radiation and chemotherapy. The major obstacles for successful remedy are invasiveness and therapy resistance of GBM cells. Invasive glioma cells leave primary tumor core and infiltrate surrounding normal brain leading to inevitable recurrence, even after surgical resection, radiation and chemotherapy. Therapy resistance allowing for selection of more aggressive and resistant sub-populations including GBM stem-like cells (GSCs) upon treatment is another serious impediment to successful treatment. Through their regulation of multiple genes, microRNAs can orchestrate complex programs of gene expression and act as master regulators of cellular processes. MicroRNA-based therapeutics could thus impact broad cellular programs, leading to inhibition of invasion and sensitization to radio/chemotherapy. Our data show that miR-451 attenuates glioma cell migration in vitro and invasion in vivo. In addition, we have found that miR-451 sensitizes glioma cells to conventional chemo- and radio-therapy. Our data also show that miR-451 is regulated in vivo by AMPK pathway and that AMPK/miR-451 loop has the ability to switch between proliferative and migratory pattern of glioma cells behavior. We therefore postulate that AMPK/miR-451 negative reciprocal feedback loop allows GBM cells/GSCs to adapt to tumor “ecosystem” by metabolic and behavioral flexibility, and that disruption of such a loop reduces invasiveness and diminishes therapy resistance.