A Putative Hsa-miR-582-5p–CD81 Relationship Identified by Integrative Transcriptomic Analysis in Osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents, and outcomes for metastatic disease have remained poor, highlighting the need for molecular biomarkers. We integrated three Gene Expression Omnibus (GEO) mRNA expression datasets (GSE12865, GSE14359, and GSE246405) to identify differentially expressed genes (DEGs) between OS and non-malignant bone-related controls. Overlapping DEGs were used to build a protein-protein interaction network, and hub genes were prioritized using multiple network topology algorithms. Prognostic associations were evaluated using the R2 Genomics Platform. Putative upstream miRNAs targeting the top candidate were obtained from prediction databases and intersected with dysregulated circulating miRNAs from GSE65071 (localized OS plasma vs. healthy controls). Functional enrichment analyses (Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and cancer hallmarks) were performed to contextualize the candidate signature. We identified 107 overlapping DEGs and prioritized eight hub genes. <i>CD81</i> was significantly associated with overall survival (Bonferroni-adjusted <i>p</i> = 0.043) and showed reduced expression in OS tissues and cell line models. hsa-miR-582-5p was nominated as a candidate miRNA predicted to target <i>CD81</i> and was upregulated in OS plasma. Enrichment results linked the signature to angiogenesis, extracellular matrix remodeling, focal adhesion, and metastasis-associated signatures. These findings support <i>CD81</i> as a candidate prognostic biomarker and nominate a putative hsa-miR-582-5p-<i>CD81</i> relationship for future validation.