Identification of key miRNA signature and pathways involved in multiple myeloma by integrated bioinformatics analysis

Multiple myeloma (MM) is one of the most common types of hematologic malignancy for which the underlying molecular mechanisms remain largely unclear. Dysregulated miRNA expression has been shown to be involved in MM tumorigenesis, progression and drug response. Therefore, a comprehensive analysis based on miRNA-level integrated strategy was performed. This study aimed to elucidate key miRNA signatures and pathways in MM by integrated bioinformatics analysis. Expression profiles GSE24371, GSE49261 and GSE54156 were obtained from the Gene Expression Omnibus database, and differentially expressed miRNAs (DEMirs) with p and discussion: First, six up-regulated and four down-regulated DEMirs shared between any two GSE data sets were identified. Second, target genes (DEMirTGs) by up-regulated and down-regulated DEMirs were obtained. Functional and subpathway enrichment analysis showed that these up-regulated DEMirs are consistently involved in the Wnt signaling pathway. Moreover, enrichment of the down-regulated DEMirs is mainly in the MAPK signaling pathway. Finally, a protein–protein interaction sub-network for these DEMirTGs was constructed, the correlations between the two key genes were identified and survival in MM was evaluated using multiple independent data sets. We identified miRNA signatures and key target genes that were closely related to MM biology, and these genes might serve as potential therapeutic targets for MM patients.

多发性骨髓瘤（Multiple myeloma, MM）是最常见的血液系统恶性肿瘤之一，其潜在分子机制目前仍未完全阐明。异常表达的微小RNA（microRNA, miRNA）已被证实参与MM的肿瘤发生、疾病进展及药物应答过程。因此，本研究采用基于miRNA水平的整合分析策略开展了系统性综合分析，旨在通过整合生物信息学分析，阐明MM发生发展中的关键miRNA分子标记物及相关通路。
本研究从基因表达综合数据库（Gene Expression Omnibus, GEO）获取了GSE24371、GSE49261与GSE54156三套表达谱数据，并筛选得到差异表达miRNA（differentially expressed miRNAs, DEMirs），具体分析如下：首先，鉴定出任意两套GSE数据集共有的6个上调差异表达miRNA及4个下调差异表达miRNA；其次，获取了上调及下调差异表达miRNA对应的靶基因（differentially expressed miRNA target genes, DEMirTGs）。功能富集与亚通路富集分析结果显示，上调差异表达miRNA显著富集于Wnt信号通路（Wnt signaling pathway），而下调差异表达miRNA则主要富集于MAPK信号通路（MAPK signaling pathway）；最后，构建了上述DEMirTGs的蛋白质-蛋白质相互作用子网，鉴定出两个关键基因间的表达关联，并利用多套独立数据集评估了MM患者的生存预后情况。
本研究鉴定出与MM生物学行为密切相关的miRNA分子标记物及关键靶基因，这些基因或可作为MM患者潜在的治疗靶点。