Partners Multiple Sclerosis Center, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Ann Neurol. 2013 Jun;73(6):729-40. doi: 10.1002/ana.23880. Epub 2013 Jul 8.
MicroRNAs (miRNAs) are single-stranded, small noncoding RNAs that regulate gene expression. Because they are stable in serum, they are being developed as biomarkers for cancer and other diseases. In multiple sclerosis (MS), miRNAs have been studied in cell populations but not in the circulation. In MS, a major challenge is to develop immune biomarkers to monitor disease. We asked whether circulating miRNAs could be identified in MS and whether they are linked to disease stage and/or disability.
A total of 368 miRNAs were measured in ethylenediaminetetraacetic acid plasma in 10 relapsing-remitting MS (RRMS) patients, 9 secondary progressive MS (SPMS) patients, and 9 healthy controls (HCs) using miRCURY LNA™ Universal RT microRNA polymerase chain reaction panels. Nineteen miRNAs from this discovery set were validated using qPCR on an independent set of 50 RRMS patients, 51 SPMS patients, and 32 HCs.
We found that circulating miRNAs are differentially expressed in RRMS and SPMS versus HCs and in RRMS versus SPMS. We also found miRNAs to be linked to Expanded Disability Status Scale (EDSS). hsa-miR-92a-1* was identified in the largest number of comparisons. It was different in RRMS versus SPMS, and RRMS versus HCs, and showed an association with EDSS and disease duration. miR-92 has target genes involved in cell cycle regulation and cell signaling. The let-7 family of miRNAs differentiated SPMS from HCs and RRMS from SPMS. let-7 miRNAs regulate stem cell differentiation and T cell activation, activate Toll-like receptor 7, and are linked to neurodegeneration. hsa-miR-454 differentiated RRMS from SPMS, and hsa-miR-145 differentiated RRMS from HCs and RRMS from SPMS. Interestingly, the same circulating miRNAs (let-7 and miR-92) that were differentially expressed in RRMS versus SPMS also differentiated amyotrophic lateral sclerosis (ALS) from RRMS subjects, but were not different between SPMS and ALS, suggesting that similar processes may occur in SPMS and ALS.
Our results establish circulating miRNAs as a readily accessible blood biomarker to monitor disease in MS.
微小 RNA（miRNA）是一种单链、小的非编码 RNA，可调节基因表达。由于它们在血清中稳定，因此它们被开发为癌症和其他疾病的生物标志物。在多发性硬化症（MS）中，已经在细胞群中研究了 miRNA，但在循环中尚未研究。在 MS 中，一个主要的挑战是开发免疫生物标志物来监测疾病。我们想知道是否可以在 MS 中鉴定出循环 miRNA，以及它们是否与疾病阶段和/或残疾有关。
使用 miRCURY LNA™ Universal RT microRNA 聚合酶链反应试剂盒，在 10 名复发缓解型 MS（RRMS）患者、9 名继发进展型 MS（SPMS）患者和 9 名健康对照（HC）的 EDTA 血浆中测量了 368 种 miRNA。在一个独立的 50 名 RRMS 患者、51 名 SPMS 患者和 32 名 HC 患者的独立队列中，使用 qPCR 对发现集的 19 种 miRNA 进行了验证。
我们发现循环 miRNA 在 RRMS 和 SPMS 与 HCs 之间以及 RRMS 与 SPMS 之间存在差异表达。我们还发现 miRNA 与扩展残疾状况量表（EDSS）有关。hsa-miR-92a-1* 在大多数比较中被识别。它在 RRMS 与 SPMS 之间以及 RRMS 与 HCs 之间存在差异，并与 EDSS 和疾病持续时间有关。miR-92 有参与细胞周期调控和细胞信号转导的靶基因。let-7 家族 miRNA 区分了 SPMS 与 HCs 和 RRMS 与 SPMS。let-7 miRNA 调节干细胞分化和 T 细胞激活，激活 Toll 样受体 7，并与神经退行性变有关。hsa-miR-454 区分了 RRMS 与 SPMS，hsa-miR-145 区分了 RRMS 与 HCs 和 RRMS 与 SPMS。有趣的是，在 RRMS 与 SPMS 之间差异表达的相同循环 miRNA（let-7 和 miR-92）也将肌萎缩侧索硬化症（ALS）与 RRMS 患者区分开来，但在 SPMS 与 ALS 之间没有差异，这表明类似的过程可能发生在 SPMS 和 ALS 中。
我们的研究结果确立了循环 miRNA 作为监测 MS 疾病的一种易于获得的血液生物标志物。
