Department of Radiation Oncology, Tianjin Hospital, 406 Jiefangnan Road, Tianjin, 300211, People's Republic of China.
Department of Radiation Oncology, PLA Airforce General Hospital of Anhui Medical University, Beijing, 100142, People's Republic of China.
Cell Oncol (Dordr). 2018 Feb;41(1):25-33. doi: 10.1007/s13402-017-0355-3. Epub 2017 Oct 26.
Exosomal miRNAs that play an important role in cell-cell communication have attracted major attention as potential diagnostic and prognostic biomarkers for various cancers. The aim of this study was to determine the diagnostic/prognostic significance of serum exosomal miR-301a in glioma patients.
Quantitative real-time PCR was used to determine the serum exosomal expression levels of miR-301a. Kaplan-Meier survival analyses, Cox regression analyses and ROC working curve analyses were applied to assess the diagnostic and prognostic values of miR-301a in glioma patients. Also, several in vitro assays were used, including proliferation, invasion and cell signaling assays.
First, we established that serum exosomal miR-301a extracted from grade IV glioblastoma (GBM) patients was biologically active, i.e., promoted the proliferation and invasion of glioma-derived H4 cells. Subsequently, we found that serum exosomal miR-301a levels were significantly up-regulated in glioma patients compared to healthy controls. Additionally, we found that increased serum exosomal miR-301a levels were correlated with ascending pathological grades and lower Karnofsky performance status (KPS) scores. Importantly, we also found that the serum exosomal miR-301a levels were significantly reduced after surgical resection of primary tumors and increased again during GBM recurrence. Kaplan-Meier analysis of patients with an advanced pathological grade (III or IV) and an increased serum exosomal miR-301a level revealed a longer overall survival (OS) compared to those with a lower level (p < 0.01). Both univariate and multivariate Cox regression analyses confirmed that serum exosomal miR-301a levels are independently associated with OS. Finally, we found that miR-301a may activate the AKT and FAK signaling pathways by down regulating PTEN.
Our data indicate that serum exosomal miR-301a levels may reflect the cancer-bearing status and pathological changes in glioma patients. Serum exosomal miR-301a expression may serve as a novel biomarker for glioma diagnosis and as a prognostic factor for advanced grade disease.
在细胞间通讯中发挥重要作用的细胞外体 miRNA 作为各种癌症的潜在诊断和预后生物标志物引起了广泛关注。本研究旨在确定血清外泌体 miR-301a 在神经胶质瘤患者中的诊断/预后意义。
采用实时定量 PCR 法测定血清外泌体 miR-301a 的表达水平。应用 Kaplan-Meier 生存分析、Cox 回归分析和 ROC 工作曲线分析评估 miR-301a 在神经胶质瘤患者中的诊断和预后价值。还进行了几项体外检测，包括增殖、侵袭和细胞信号转导检测。
首先，我们确定从 IV 级神经胶质瘤（GBM）患者中提取的血清外泌体 miR-301a 是有生物活性的，即促进神经胶质瘤源性 H4 细胞的增殖和侵袭。随后，我们发现与健康对照组相比，神经胶质瘤患者的血清外泌体 miR-301a 水平显著升高。此外，我们发现血清外泌体 miR-301a 水平升高与病理分级升高和卡氏功能状态评分（KPS）降低相关。重要的是，我们还发现，原发性肿瘤切除后，血清外泌体 miR-301a 水平显著降低，GBM 复发后再次升高。对高级别病理（III 级或 IV 级）患者进行 Kaplan-Meier 分析，结果显示，与低水平患者相比，高水平患者的总生存期（OS）更长（p<0.01）。单因素和多因素 Cox 回归分析均证实，血清外泌体 miR-301a 水平与 OS 独立相关。最后，我们发现 miR-301a 通过下调 PTEN 可能激活 AKT 和 FAK 信号通路。
我们的数据表明，血清外泌体 miR-301a 水平可能反映神经胶质瘤患者的肿瘤状态和病理变化。血清外泌体 miR-301a 表达可作为神经胶质瘤诊断的新生物标志物，也是高级别疾病的预后因素。
