Deciphering the Role of KIF18A in Osteosarcoma Progression: An Integrative Analysis and Experimental Validation

Osteosarcoma (OS) is a highly aggressive primary bone malignancy with a prominent propensity for metastasis. The identification of the key molecular drivers for OS progression is paramount to developing effective therapies. Although kinesin family member 18A (KIF18A) has previously been suggested to play a role as a potential oncogene in the development and metastatic progression of several types of cancer, little is known about its exact functional role in OS.

OS datasets were retrieved from the GSE126209 database and the TARGET dataset, with a focus on expression data of kinesin family genes. Differential expression analysis of these genes was conducted using R, comparing tumor tissues to paired adjacent non-tumor tissues, as well as between metastatic and non-metastatic cases. In order to illuminate the functional mechanism, pathway enrichment analysis was executed through Gene Set Enrichment Analysis (GSEA), and the tumor immune microenvironment composition was analyzed comprehensively using the CIBERSORT algorithm. Functional experiments were conducted to investigate the effects of OS KIF18A on cell behaviors. In vivo experiments were used to identify the function of KIF18A on tumor growth. In addition, drug sensitivity profiling and analysis of the lncRNA-mediated regulatory network were implemented to seek possible therapeutic relevance.

Analysis of the kinesin family gene expression in the GSE126209 OS dataset revealed that KIF18A is markedly upregulated in tumor tissues compared to normal counterparts. Further analysis of the TARGET database indicated that elevated KIF18A expression is associated with metastatic OS, a finding that was validated using clinical samples from OS patients. Our functional assay indicated that KIF18A increased proliferation, invasion, and migration activity of OS cells in vitro and inhibited apoptosis. In line with this, the knockdown of KIF18A remarkably suppressed tumor growth in OS xenograft models in vivo. Pathway enrichment analysis revealed dysregulation of several key signaling pathways associated with KIF18A expression, providing mechanistic insights into its oncogenic role. Immune profiling indicated that high KIF18A expression was linked to an immunosuppressive tumor microenvironment. Furthermore, drug sensitivity analysis indicated that lower KIF18A expression was associated with a higher sensitivity to lapatinib. Additionally, a set of lncRNAs associated with KIF18A expression was identified, implicating potential regulatory networks involved in OS progression.

This study reveals that KIF18A is upregulated in OS, particularly in metastatic cases, and is linked to poor clinical outcomes. Functional experiments confirm that KIF18A promotes proliferation, migration, and invasion of OS cells while suppressing apoptosis. In vivo experiments reveal that KIF18A knockdown strongly inhibits tumor growth. KIF18A expression correlates with dysregulation of key oncogenic pathways, an immunosuppressive microenvironment, and potential immunotherapy resistance. These results highlight KIF18A's role as a pivotal oncogene in OS progression and suggest its promise as both a prognostic biomarker and a therapeutic target.