School of Engineering, Dali University, Dali, Yunnan, China.
School of Information Technology and Mathematical Sciences, University of South Australia, Mawson Lakes, SA, Australia.
Bioinformatics. 2018 Dec 15;34(24):4232-4240. doi: 10.1093/bioinformatics/bty525.
MicroRNAs (miRNAs) are small non-coding RNAs with the length of ∼22 nucleotides. miRNAs are involved in many biological processes including cancers. Recent studies show that long non-coding RNAs (lncRNAs) are emerging as miRNA sponges, playing important roles in cancer physiology and development. Despite accumulating appreciation of the importance of lncRNAs, the study of their complex functions is still in its preliminary stage. Based on the hypothesis of competing endogenous RNAs (ceRNAs), several computational methods have been proposed for investigating the competitive relationships between lncRNAs and miRNA target messenger RNAs (mRNAs). However, when the mRNAs are released from the control of miRNAs, it remains largely unknown as to how the sponge lncRNAs influence the expression levels of the endogenous miRNA targets.
We propose a novel method to construct lncRNA related miRNA sponge regulatory networks (LncmiRSRNs) by integrating matched lncRNA and mRNA expression profiles with clinical information and putative miRNA-target interactions. Using the method, we have constructed the LncmiRSRNs for four human cancers (glioblastoma multiforme, lung cancer, ovarian cancer and prostate cancer). Based on the networks, we discover that after being released from miRNA control, the target mRNAs are normally up-regulated by the sponge lncRNAs, and only a fraction of sponge lncRNA-mRNA regulatory relationships and hub lncRNAs are shared by the four cancers. Moreover, most sponge lncRNA-mRNA regulatory relationships show a rewired mode between different cancers, and a minority of sponge lncRNA-mRNA regulatory relationships conserved (appearing) in different cancers may act as a common pivot across cancers. Besides, differential and conserved hub lncRNAs may act as potential cancer drivers to influence the cancerous state in cancers. Functional enrichment and survival analysis indicate that the identified differential and conserved LncmiRSRN network modules work as functional units in biological processes, and can distinguish metastasis risks of cancers. Our analysis demonstrates the potential of integrating expression profiles, clinical information and miRNA-target interactions for investigating lncRNA regulatory mechanism.
LncmiRSRN is freely available (https://github.com/zhangjunpeng411/LncmiRSRN).
Supplementary data are available at Bioinformatics online.
微小 RNA（miRNAs）是长度约为 22 个核苷酸的小非编码 RNA。miRNAs 参与包括癌症在内的许多生物学过程。最近的研究表明，长非编码 RNA（lncRNAs）作为 miRNA 海绵出现，在癌症生理学和发展中发挥重要作用。尽管人们越来越认识到 lncRNAs 的重要性，但对其复杂功能的研究仍处于初步阶段。基于竞争内源性 RNA（ceRNA）假说，已经提出了几种计算方法来研究 lncRNA 与 miRNA 靶信使 RNA（mRNA）之间的竞争关系。然而，当 mRNA 不受 miRNA 控制时，海绵 lncRNA 如何影响内源性 miRNA 靶基因的表达水平在很大程度上仍然未知。
我们通过整合匹配的 lncRNA 和 mRNA 表达谱以及临床信息和假定的 miRNA 靶相互作用，提出了一种构建 lncRNA 相关 miRNA 海绵调节网络（LncmiRSRN）的新方法。使用该方法，我们构建了四种人类癌症（胶质母细胞瘤、肺癌、卵巢癌和前列腺癌）的 LncmiRSRN。基于这些网络，我们发现，在受到 miRNA 控制后，靶 mRNAs 通常会被海绵 lncRNA 上调，并且只有一部分海绵 lncRNA-mRNA 调节关系和 hub lncRNA 被四种癌症共享。此外，大多数海绵 lncRNA-mRNA 调节关系在不同癌症之间呈现出重新布线的模式，而不同癌症中保守（出现）的少数海绵 lncRNA-mRNA 调节关系可能作为癌症之间的共同枢轴发挥作用。此外，差异和保守的 hub lncRNA 可能作为潜在的癌症驱动因素，影响癌症中的癌症状态。功能富集和生存分析表明，所鉴定的差异和保守的 LncmiRSRN 网络模块作为生物学过程中的功能单元发挥作用，并可以区分癌症的转移风险。我们的分析表明，整合表达谱、临床信息和 miRNA 靶相互作用可用于研究 lncRNA 调节机制。
LncmiRSRN 可免费获得（https://github.com/zhangjunpeng411/LncmiRSRN）。
补充数据可在《生物信息学》在线获取。
