Transcriptome analysis reveals crucial oncogenic and tumor suppressor miRNAs in lung adenocarcinoma

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.