Chaturvedi Aparna, Som Anup
Biocomputing Research Laboratory, Centre of Bioinformatics, Institute of Interdisciplinary Studies, University of Allahabad, Prayagraj 211002, India.
Biocomputing Research Laboratory, Centre of Bioinformatics, Institute of Interdisciplinary Studies, University of Allahabad, Prayagraj 211002, India.
Lung Cancer. 2025 Aug;206:108540. doi: 10.1016/j.lungcan.2025.108540. Epub 2025 Apr 17.
MicroRNAs (miRNAs) play essential roles in post-transcriptional gene regulation and are increasingly recognized as key regulators in various diseases. This study aimed to identify the key miRNA biomarkers and decodes their regulatory mechanism involved in human lung adenocarcinoma (LUAD) using network-based integrative multi-omics approaches.
We applied Weighted Gene Co-expression Network Analysis (WGCNA) method on miRNA-Seq data to detect key miRNA modules that correlated with the disease traits. Then we used differential expression profile, level of gene significance, module-trait relationship, target-identification, gene set enrichment analysis (GSEA), and survival analysis approaches to decipher LUAD critical miRNAs.
Our analysis demonstrated a core set of LUAD critical miRNAs (called as LCmiRs) that comprises 33 oncogenic and 17 tumor suppressor miRNAs. These key miRNAs were then mapped to their target mRNAs through atarget-identification approach, allowing for the construction of miRNA-mRNA interaction networks that revealed critical regulatory relationships. The GSEA results showed that upregulated mRNAs, those were targets of downregulated miRNAs (i.e., tumor suppressor miRNAs), were predominantly associated with pathways related to cell division, oocyte maturation/meiosis, TGF-beta signalling pathway, and metabolic processes, while downregulated mRNAs, those were targets of upregulated miRNAs (i.e., oncogenic miRNAs), were linked to angiogenesis, negative regulation of growth, and receptor-mediated signaling. Validation of the identified oncogenic/tumor-suppressor miRNAs reported five novel miRNAs. Among these, the oncogenic miRNAs are hsa-miR-18a-3p, hsa-miR-589-3p, hsa-miR-1229-3p, and hsa-miR-3651, and tumor suppressor one is hsa-miR-618.
This study provides a systematic in silico framework for identifying LUAD associated miRNAs. The discovery of five novel miRNAs highlights their potential as diagnostic biomarkers and therapeutic targets, offering valuable insights for experimental and clinical investigations in LUAD.
微小RNA（miRNA）在转录后基因调控中发挥着重要作用，并且越来越被认为是各种疾病的关键调节因子。本研究旨在使用基于网络的综合多组学方法，鉴定人类肺腺癌（LUAD）中的关键miRNA生物标志物，并解码其调控机制。
我们对miRNA测序数据应用加权基因共表达网络分析（WGCNA）方法，以检测与疾病特征相关的关键miRNA模块。然后，我们使用差异表达谱、基因显著性水平、模块-性状关系、靶点鉴定、基因集富集分析（GSEA）和生存分析方法来解读LUAD关键miRNA。
我们的分析证明了一组LUAD关键miRNA（称为LCmiRs），其中包括33个致癌miRNA和17个肿瘤抑制miRNA。然后通过靶点鉴定方法将这些关键miRNA映射到其靶mRNA上，从而构建miRNA-mRNA相互作用网络，揭示关键调控关系。GSEA结果表明，上调的mRNA（即下调miRNA的靶点，也就是肿瘤抑制miRNA的靶点）主要与细胞分裂、卵母细胞成熟/减数分裂、TGF-β信号通路和代谢过程相关的途径有关，而下调的mRNA（即上调miRNA的靶点，也就是致癌miRNA的靶点）则与血管生成、生长的负调控和受体介导的信号传导有关。对鉴定出的致癌/肿瘤抑制miRNA的验证报告了5个新的miRNA。其中，致癌miRNA为hsa-miR-18a-3p、hsa-miR-589-3p、hsa-miR-1229-3p和hsa-miR-3651，肿瘤抑制miRNA为hsa-miR-618。
本研究为鉴定LUAD相关miRNA提供了一个系统的计算机框架。5个新miRNA的发现突出了它们作为诊断生物标志物和治疗靶点的潜力，为LUAD的实验和临床研究提供了有价值的见解。
