Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan.
PLoS One. 2019 Jan 7;14(1):e0210400. doi: 10.1371/journal.pone.0210400. eCollection 2019.
MicroRNAs (miRNAs) are small RNA molecules that inhibit gene function by suppressing translation of target genes. However, in primary central nervous system lymphoma (PCNSL), the biological significance of miRNAs is largely unknown, although some miRNAs are known to be prognosis markers. Here, we analyzed 847 miRNAs expressed in 27 PCNSL specimens using microarray profiling and surveyed miRNA signature for prognostic prediction. Of these, 16 miRNAs were expressed in 27 PCNSL specimens at a frequency of 48%. Their variable importance measured by Random forest model revealed miR-192, miR-486, miR-28, miR-52, miR-181b, miR-194, miR-197, miR-93, miR-708, and let-7g as having positive effects; miR-29b-2*, miR-126, and miR-182 as having negative effects; and miR-18a*, miR-425, and miR-30d as neutral. After principal component analysis, the prediction formula for prognosis, consisting of the expression values of the above-mentioned miRNAs, clearly divided Kaplan-Meier survival curves by the calculated Z-score (HR = 6.4566, P = 0.0067). The 16 miRNAs were enriched by gene ontology terms including angiogenesis, cell migration and proliferation, and apoptosis, in addition to signaling pathways including TGF-β/SMAD, Notch, TNF, and MAPKinase. Their target genes included BCL2-related genes, HMGA2 oncogene, and LIN28B cancer stem cell marker. Furthermore, three miRNAs including miR-181b, miR-30d, and miR-93, selected from the 16 miRNAs, also showed comparable results for survival (HR = 8.9342, P = 0.0007), suggestive of a miRNA signature for prognostic prediction in PCNSL. These results indicate that this miRNA signature is useful for prognostic prediction in PCNSL and would help us understand target pathways for therapies in PCNSL.
微小 RNA（miRNA）是通过抑制靶基因翻译来抑制基因功能的小 RNA 分子。然而，在原发性中枢神经系统淋巴瘤（PCNSL）中，miRNA 的生物学意义在很大程度上尚不清楚，尽管一些 miRNA 被认为是预后标志物。在这里，我们使用微阵列分析对 27 个 PCNSL 标本中的 847 个 miRNA 进行了分析，并调查了 miRNA 特征以进行预后预测。其中，16 个 miRNA 在 27 个 PCNSL 标本中的表达频率为 48%。随机森林模型测量的它们的变量重要性揭示了 miR-192、miR-486、miR-28、miR-52、miR-181b、miR-194、miR-197、miR-93、miR-708 和 let-7g 具有正效应；miR-29b-2*、miR-126 和 miR-182 具有负效应；而 miR-18a*、miR-425 和 miR-30d 则为中性。在主成分分析后，由上述 miRNA 的表达值组成的用于预测预后的公式，根据计算的 Z 分数（HR = 6.4566，P = 0.0067）清楚地划分了 Kaplan-Meier 生存曲线。除了 TGF-β/SMAD、Notch、TNF 和 MAPKinase 等信号通路外，这些 miRNA 还通过包括血管生成、细胞迁移和增殖以及细胞凋亡在内的基因本体术语进行富集。它们的靶基因包括 BCL2 相关基因、HMGA2 癌基因和 LIN28B 癌症干细胞标记物。此外，从 16 个 miRNA 中选择的三个 miRNA（miR-181b、miR-30d 和 miR-93）的生存结果也具有可比性（HR = 8.9342，P = 0.0007），提示 PCNSL 中存在用于预后预测的 miRNA 特征。这些结果表明，这种 miRNA 特征可用于 PCNSL 的预后预测，并有助于我们了解 PCNSL 治疗的靶途径。
