长非编码 RNA LINC01503 预测胶质瘤预后不良，并通过激活 Wnt/β-连环蛋白信号通路促进肿瘤发生和进展。
Long non-coding RNA LINC01503 predicts worse prognosis in glioma and promotes tumorigenesis and progression through activation of Wnt/β-catenin signaling.
机构信息
Department of Neurosurgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China.
出版信息
Eur Rev Med Pharmacol Sci. 2019 Feb;23(4):1600-1609. doi: 10.26355/eurrev_201902_17119.
OBJECTIVE
Long-noncoding RNAs (lncRNAs) have been recently shown to be involved in the regulation of numerous biological processes including tumor progression. In this study, we aimed to explore the role of lncRNA LINC01503 (LINC01503) in the development and progression of glioma.
PATIENTS AND METHODS
Relative levels of LINC01503 were evaluated in tumor tissues from 133 patients with glioma as well as from cultured glioma cell lines. The correlation among LINC01503 levels, pathological types, and survivals of glioma patients were also determined using the Kaplan-Meier method and multivariate analysis. Next, we investigated the effect of LINC01503 on the proliferation, colony formation, apoptosis, migration and invasion in the U251 and LN299 cells. Relative protein expression was analyzed by Western blot assays.
RESULTS
We found that LINC01503 expression level was significantly up-regulated in glioma tissue and cells, and that its overexpression was significantly correlated with KPS, tumor size and WHO grade in glioma patients. Kaplan-Meier analysis showed that patients with higher levels of LINC01503 had significantly poorer overall survival and disease-free survival than those with lower expression of this lncRNA in glioma patients. Multivariate analysis further confirmed that LINC01503 is an independent prognostic factor in patients with glioma. Functional assays with in vitro showed that knockdown of LINC01503 in the U251 and LN299 cell lines suppressed cells growth, colony formation, invasion and migration, and promoted apoptosis. Mechanistic investigation showed that LINC01503 can modulate Wnt/β-catenin signaling, as determined by that knockdown of LINC01503 decreased the TOP-FLASH activity and β-catenin, cyclin D1 and c-myc.
CONCLUSIONS
Our findings suggested that LINC01503 conferred oncogenic function in glioma and may be a new prognostic biomarker and novel therapeutic strategy for this malignancy.
目的
长链非编码 RNA（lncRNA）最近被证明参与了许多生物学过程的调控，包括肿瘤的进展。在这项研究中，我们旨在探讨 lncRNA LINC01503（LINC01503）在神经胶质瘤发生和发展中的作用。
方法
评估了 133 例神经胶质瘤患者肿瘤组织和培养的神经胶质瘤细胞系中 LINC01503 的相对水平。采用 Kaplan-Meier 法和多因素分析确定 LINC01503 水平与神经胶质瘤患者病理类型和生存的相关性。接下来，我们研究了 LINC01503 对 U251 和 LN299 细胞增殖、集落形成、凋亡、迁移和侵袭的影响。通过 Western blot 分析检测相对蛋白表达。
结果
我们发现 LINC01503 在神经胶质瘤组织和细胞中的表达水平显著上调，其过表达与神经胶质瘤患者的 KPS、肿瘤大小和 WHO 分级显著相关。Kaplan-Meier 分析显示，LINC01503 水平较高的患者总体生存率和无病生存率明显低于 LINC01503 低表达的患者。多因素分析进一步证实，LINC01503 是神经胶质瘤患者的独立预后因素。体外功能实验显示，U251 和 LN299 细胞系中 LINC01503 的敲低抑制了细胞生长、集落形成、侵袭和迁移，并促进了细胞凋亡。机制研究表明，LINC01503 可以调节 Wnt/β-catenin 信号通路，LINC01503 的敲低降低了 TOP-FLASH 活性和β-catenin、cyclin D1 和 c-myc。
结论
我们的研究结果表明，LINC01503 在神经胶质瘤中发挥致癌作用，可能是该恶性肿瘤的一种新的预后标志物和新的治疗策略。
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