Wang Xiaxia, Ding Yanrui, Wang Jie, Wu Yanyan
School of Science, Jiangnan University, Wuxi, China.
Laboratory of Media Design and Software Technology, Jiangnan University, Wuxi, China.
Front Genet. 2020 Jan 28;10:1398. doi: 10.3389/fgene.2019.01398. eCollection 2019.
Bladder cancer is the most common malignant tumor of the urinary system, and it has high incidence, high degree of malignancy, and easy recurrence after surgery. The etiology and pathogenesis of bladder cancer are not fully understood, but more and more studies have shown that its development may be regulated by some core molecules. To identify key molecules in bladder cancer, we constructed a three-layer network by merging lncRNA-miRNA regulatory network, miRNA-mRNA regulatory network, and lncRNA-mRNA coexpression network, and further analyzed the topology attributes of the network including the degree, betweenness centrality and closeness centrality of nodes. We found that miRNA-93 and miRNA-195 are controllers for a three-layer network and regulators of numerous target genes associated with bladder cancer. Functional enrichment analysis of their target mRNAs revealed that miRNA-93 and miRNA-195 may be closely related to bladder cancer by disturbing the homeostasis of the cell cycle or HTLV-I infection. In addition, since E2F1 and E2F2 are enriched in various KEGG signaling pathways, we conclude that they are important target genes of miRNA-93, and participate in the apoptotic process by forming a complex with a certain protein or transcription factor activity, sequence-specific DNA binding in bladder cancer. Similarly, AKT3 is an important target gene of miRNA-195, its expression is associated with PI3K-Akt-mTOR signaling pathway and AMPK-mTOR signaling pathway. Therefore, we speculate that AKT3 may participate in proliferation and apoptosis of bladder cancer cells through these pathways, and ultimately affect the biological behavior of tumor cells. Furthermore, through survival analysis, we found that miRNA-195 and miRNA-93 are associated with poor prognosis of bladder cancer. And the Kaplan-Meier curve showed that 24 mRNAs and nine lncRNAs are closely related to overall survival of bladder cancer.
膀胱癌是泌尿系统最常见的恶性肿瘤，具有发病率高、恶性程度高、术后易复发的特点。膀胱癌的病因和发病机制尚未完全明确，但越来越多的研究表明其发展可能受一些核心分子调控。为了鉴定膀胱癌中的关键分子，我们通过合并lncRNA-miRNA调控网络、miRNA-mRNA调控网络和lncRNA-mRNA共表达网络构建了一个三层网络，并进一步分析了该网络的拓扑属性，包括节点的度、介数中心性和紧密中心性。我们发现miRNA-93和miRNA-195是三层网络的调控因子以及众多与膀胱癌相关的靶基因的调节因子。对其靶mRNA的功能富集分析表明，miRNA-93和miRNA-195可能通过扰乱细胞周期稳态或HTLV-I感染与膀胱癌密切相关。此外，由于E2F1和E2F2在各种KEGG信号通路中富集，我们得出结论，它们是miRNA-93的重要靶基因，并通过与某种蛋白质形成复合物或转录因子活性、在膀胱癌中序列特异性DNA结合参与凋亡过程。同样，AKT3是miRNA-195的重要靶基因，其表达与PI3K-Akt-mTOR信号通路和AMPK-mTOR信号通路相关。因此，我们推测AKT3可能通过这些途径参与膀胱癌细胞的增殖和凋亡，最终影响肿瘤细胞的生物学行为。此外，通过生存分析，我们发现miRNA-195和miRNA-93与膀胱癌的不良预后相关。并且Kaplan-Meier曲线显示，24个mRNA和9个lncRNA与膀胱癌的总生存密切相关。
