Department of Neurosurgery, Iran University of Medical Sciences, Tehran, Iran.
Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
Clin Neurol Neurosurg. 2020 Mar;190:105652. doi: 10.1016/j.clineuro.2019.105652. Epub 2019 Dec 27.
Glioblastoma (GBM) is the most common primary malignant neoplasm of the central nervous system (CNS). Despite the progress in therapeutic strategies such as surgical techniques, radiotherapy, chemotherapy, and targeted therapy, prognosis and therapeutically convenient monitoring tools in patients with GBM has not improved significantly up to now.Therefore, exosomal miRNAs as novel non-invasive biomarkers having high sensitivity and specificity are required to improve diagnosis and to develop new targeted therapy strategies for GBM patients. The aim of the present study was to investigate a novel miRNA signature as a predictive biomarker for diagnosis and measurement of response to therapeutic interventions in plasma of GBM patients versus traumatic brain injury and diffuse low-grade astrocytoma (LGA) patients.
Plasma exosomal-microRNAs were isolated from GBM (n = 25), LGA (n = 25), and head trauma patients (n = 15) as non-glioma control from March 2017 to June 2018 in Department of Neurosurgery at Rasoul-e-Akram Hospital. Through a bioinformatics analysis, we used Miranda, TargetScan, mirBase, DIANA-microT-CDS, and KEGG database as well as microarray data analysis from GEO for microRNA candidates. Finally, miR-210, miR-185, miR-5194, and miR-449 were selected among those miRNAs because they were recorded to target the maximum number of genes in EGFR and c-MET signaling pathways. Then, exosomal microRNAs were extracted from plasma of patients and quantitated by locked nucleic acid real-time PCR in GBM, LGA, and trauma patients.
This result is the first report on the role of circulating miR-185, miR-449, and miR-5194 in GBM compared to LGA and trauma. The plasma expression of miR-210 as an oncogenic miR was upregulated in GBM and LGA groups (P < 0.0001). Otherwise, miR-185, miR-5194, and miR-449 were significantly downregulated (P ≤ 0.05) in GBM and LGA compared to trauma patients. There was no significant downregulation in the expression of miR-185 between GBM and LGA, while the expression of miR-5194 (P ≤ 0.05) and miR-449 (P ≤ 0.05) was significantly decreased in GBM patients compared with LGA.
These results indicate that the levels of miR-210, miR-449, and miR-5194 are a promising diagnostic and prognostic biomarker positively correlated with histopathological grade and invasiveness of GBM. These findings imply that circulating microRNA can be potentially used as novel biomarkers for glioma that might be beneficial in clinical management of glioma patients.
胶质母细胞瘤（GBM）是中枢神经系统（CNS）最常见的原发性恶性肿瘤。尽管在治疗策略方面取得了进展，如手术技术、放疗、化疗和靶向治疗，但到目前为止，GBM 患者的预后和治疗监测工具并没有得到显著改善。因此，需要新型的外泌体 miRNAs 作为具有高灵敏度和特异性的新型非侵入性生物标志物，以改善诊断，并为 GBM 患者开发新的靶向治疗策略。本研究旨在探讨一种新型 miRNA 特征作为预测生物标志物，用于诊断和测量 GBM 患者与创伤性脑损伤和弥漫性低级别星形细胞瘤（LGA）患者对治疗干预的反应。
2017 年 3 月至 2018 年 6 月，在拉索尔阿克拉姆医院神经外科，从 GBM（n=25）、LGA（n=25）和头部创伤患者（n=15）中分离出 GBM、LGA 和创伤患者的血浆外泌体 miRNA。通过生物信息学分析，我们使用 Miranda、TargetScan、mirBase、DIANA-microT-CDS 和 KEGG 数据库以及 GEO 的 microarray 数据分析 miRNA 候选物。最后，选择 miR-210、miR-185、miR-5194 和 miR-449 作为候选 miRNA，因为它们记录了针对 EGFR 和 c-MET 信号通路中最大数量的基因。然后，从患者的血浆中提取外泌体 microRNAs，并通过Locked Nucleic Acid 实时 PCR 在 GBM、LGA 和创伤患者中定量。
这是首次报道循环 miR-185、miR-449 和 miR-5194 在 GBM 中与 LGA 和创伤相比的作用。GBM 和 LGA 组中致癌 miR-210 的血浆表达上调（P < 0.0001）。相反，miR-185、miR-5194 和 miR-449 在 GBM 和 LGA 患者与创伤患者相比显著下调（P≤0.05）。GBM 和 LGA 之间 miR-185 的表达没有明显下调，而 miR-5194（P≤0.05）和 miR-449（P≤0.05）在 GBM 患者中的表达明显低于 LGA。
这些结果表明，miR-210、miR-449 和 miR-5194 的水平是一种有前途的诊断和预后生物标志物，与 GBM 的组织病理学分级和侵袭性呈正相关。这些发现表明，循环 microRNA 可能作为新型胶质瘤生物标志物具有潜在的临床应用价值，可能有益于胶质瘤患者的临床管理。
