去甲肾上腺素通过上调 Twist1 的表达促进神经胶质瘤细胞迁移。
Norepinephrine promotes glioma cell migration through up-regulating the expression of Twist1.
机构信息
Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, #27 Taiping Road, Haidian, Beijing, 100850, China.
Laboratory Animal Center, North China University of Science and Technology, Tangshan, 063210, Hebei, China.
出版信息
BMC Cancer. 2022 Feb 26;22(1):213. doi: 10.1186/s12885-022-09330-9.
BACKGROUND
Glioma cells are characterized by high migration ability, resulting in aggressive growth of the tumors and poor prognosis of patients. It has been reported that the stress-induced hormone norepinephrine (NE) contributes to tumor progression through mediating a number of important biological processes in various cancers. However, the role of NE in the regulation of glioma migration is still unclear. Epithelial-to-mesenchymal transition (EMT) is one of the most important steps for tumor migration and metastasis. Twist1, as a key regulator of EMT, has been found to be elevated during glioma migration. But it is still unknown whether Twist1 is involved in the effect of NE on the migration of glioma cells.
METHODS
Wound healing assay and transwell assay were conducted to evaluate the migration of glioma cells upon different treatments. The mesenchymal-like phenotype and the expression of Twist1 after NE treatment were assessed by cell diameters, real-time PCR, western blot and immunofluorescence staining. The gain-and loss-of-function experiments were carried out to investigate the biological function of Twist1 in the migration induced by NE. Finally, the clinical significance of Twist1 was explored among three public glioma datasets.
RESULTS
In this study, our finding revealed a facilitative effect of NE on glioma cell migration in a β-adrenergic receptor (ADRB)-dependent way. Mechanistically, NE induced mesenchymal-like phenotype and the expression of Twist1. Twist1 overexpression promoted glioma cells migration, while knockdown of Twist1 abolished the discrepancy in the migration ability between NE treated glioma cells and control cells. In addition, the clinical analysis demonstrated that Twist1 was up-regulated in malignant gliomas and recurrent gliomas, and predicted a poor prognosis of glioma patients.
CONCLUSIONS
NE enhanced the migration ability of glioma cells through elevating the expression of Twist1. Our finding may provide potential therapeutic target for protecting patients with glioma from the detrimental effects of stress biology on the tumor progression.
背景
神经胶质瘤细胞的迁移能力很强，导致肿瘤生长迅速，患者预后不良。有报道称，应激诱导激素去甲肾上腺素（NE）通过介导多种癌症中的重要生物学过程促进肿瘤进展。然而，NE 调节神经胶质瘤迁移的作用尚不清楚。上皮间质转化（EMT）是肿瘤迁移和转移的最重要步骤之一。Twist1 作为 EMT 的关键调节因子，已发现在神经胶质瘤迁移过程中上调。但是否 Twist1 参与了 NE 对神经胶质瘤细胞迁移的影响仍不清楚。
方法
采用划痕愈合试验和 Transwell 试验评估不同处理后神经胶质瘤细胞的迁移。通过细胞直径、实时 PCR、Western blot 和免疫荧光染色评估 NE 处理后间质样表型和 Twist1 的表达。进行 gain-and loss-of-function 实验以研究 Twist1 在 NE 诱导的迁移中的生物学功能。最后，在三个公共神经胶质瘤数据集之间探索了 Twist1 的临床意义。
结果
本研究发现 NE 通过β肾上腺素能受体（ADRB）依赖性途径促进神经胶质瘤细胞迁移。机制上，NE 诱导间质样表型和 Twist1 的表达。Twist1 过表达促进神经胶质瘤细胞迁移，而敲低 Twist1 则消除了 NE 处理的神经胶质瘤细胞与对照细胞之间迁移能力的差异。此外，临床分析表明 Twist1 在恶性神经胶质瘤和复发性神经胶质瘤中上调，并预测神经胶质瘤患者预后不良。
结论
NE 通过上调 Twist1 增强神经胶质瘤细胞的迁移能力。我们的发现可能为保护神经胶质瘤患者免受应激生物学对肿瘤进展的不利影响提供潜在的治疗靶点。
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