Zhang Lu, Feng Cuihua, Zhou Yamin, Zhou Qiong
Department of Urology, Wuhan No. 6 Hospital, Wuhan, Hubei 430015, P.R. China.
Department of Gastrointestinal Surgery, Wuhan No. 6 Hospital, Wuhan, Hubei 430015, P.R. China.
Oncol Lett. 2018 Jun;15(6):9617-9624. doi: 10.3892/ol.2018.8602. Epub 2018 Apr 27.
The present study aimed to identify bladder cancer-associated microRNAs (miRNAs) and target genes, and further analyze the potential molecular mechanisms involved in bladder cancer. The mRNA and miRNA expression profiling dataset GSE40355 was downloaded from the Gene Expression Omnibus database. The Limma package in R was used to identify differential expression levels. The Human microRNA Disease Database was used to identify bladder cancer-associated miRNAs and Target prediction programs were used to screen for miRNA target genes. Enrichment analysis was performed to identify biological functions. The Database for Annotation, Visualization and Integration Discovery was used to perform OMIM_DISEASE analysis, and then protein-protein interaction (PPI) analysis was performed to identify hubs with biological essentiality. ClusterONE plugins in cytoscape were used to screen modules and the InterPro database was used to perform protein domain enrichment analysis. A group of 573 disease dysregulated genes were identified in the present study. Enrichment analysis indicated that the muscle organ development and vascular smooth muscle contraction pathways were significantly enriched in terms of disease dysregulated genes. miRNAs targets (frizzled class receptor 8, EYA transcriptional coactivator and phosphatase 4, sacsin molecular chaperone, calcium voltage-gated channel auxiliary subunit β2, peptidase inhibitor 15 and catenin α2) were mostly associated with bladder cancer. PPI analysis revealed that calmodulin 1 (CALM1), Jun proto-oncogene, AP-1 transcription factor subunit (JUN) and insulin like growth factor 1 (IGF1) were the important hub nodes. Additionally, protein domain enrichment analysis indicated that the serine/threonine protein kinase active site was enriched in module 1 extracted from the PPI network. Overall, the results suggested that the IGF signaling pathway and RAS/MEK/extracellular signal-regulated kinase transduction signaling may exert vital molecular mechanisms in bladder cancer, and that CALM1, JUN and IGF1 may be used as novel potential therapeutic targets.
本研究旨在鉴定与膀胱癌相关的微小RNA（miRNA）和靶基因，并进一步分析膀胱癌潜在的分子机制。从基因表达综合数据库下载了mRNA和miRNA表达谱数据集GSE40355。使用R语言中的Limma软件包鉴定差异表达水平。利用人类微小RNA疾病数据库鉴定与膀胱癌相关的miRNA，并使用靶标预测程序筛选miRNA靶基因。进行富集分析以鉴定生物学功能。使用注释、可视化和整合发现数据库进行OMIM_DISEASE分析，然后进行蛋白质-蛋白质相互作用（PPI）分析以鉴定具有生物学重要性的枢纽分子。使用Cytoscape中的ClusterONE插件筛选模块，并使用InterPro数据库进行蛋白质结构域富集分析。本研究鉴定出一组573个疾病失调基因。富集分析表明，疾病失调基因在肌肉器官发育和血管平滑肌收缩途径中显著富集。miRNA靶标（卷曲蛋白家族受体8、EYA转录共激活因子和磷酸酶4、伴侣蛋白sacsin、钙电压门控通道辅助亚基β2、肽酶抑制剂15和连环蛋白α2）大多与膀胱癌相关。PPI分析显示，钙调蛋白1（CALM1）、原癌基因Jun、AP-1转录因子亚基（JUN）和胰岛素样生长因子1（IGF1）是重要的枢纽节点。此外，蛋白质结构域富集分析表明，丝氨酸/苏氨酸蛋白激酶活性位点在从PPI网络提取的模块1中富集。总体而言，结果表明IGF信号通路和RAS/MEK/细胞外信号调节激酶转导信号可能在膀胱癌中发挥重要的分子机制，并且CALM1、JUN和IGF1可能作为新的潜在治疗靶点。
