Abstract
BACKGROUND: Apolipoprotein D (APOD), a member of the lipocalin superfamily, plays a pivotal role in apoptosis, cancer, immune responses, and neural injury repair. Its association with various cancer types has been well-documented, but its expression and clinical implications in oral squamous cell carcinoma (OSCC) remain underexplored. Our study aims to investigate the expression and clinical significance of APOD in OSCC. METHODS: A comprehensive analysis of APOD mRNA and protein expression in OSCC was conducted using multi-omics data from TCGA, GEO, and CPTAC databases. The findings were validated through qRT-PCR and immunohistochemistry (IHC) on OSCC tissue samples. Diagnostic and prognostic potential of APOD was assessed using summary receiver operating characteristic (sROC) curves and Kaplan-Meier survival analysis. Multivariate Cox regression analysis was performed to adjust for confounding factors and identify independent prognostic markers for survival. Gene set enrichment analysis (GSEA) was used to explore the signaling pathways associated with APOD and their biological relevance. Ethical approval for research involving human subjects was obtained from an ethics committee. RESULTS: Analysis of public databases revealed significant downregulation of both APOD mRNA and protein in OSCC tissues compared to normal mucosal controls. Results from clinical samples corroborated these findings. The sROC analysis indicated that APOD may serve as a promising diagnostic biomarker for OSCC. Multivariate Cox regression analysis identified pathological T stage as an independent prognostic factor, independent of clinical T stage and lymphovascular invasion, while APOD, although associated with prognosis, was not a robust predictor. GSEA highlighted a strong positive correlation between APOD expression and key components of Type I interferon signaling (JAK1, TYK2, STAT2), suggesting that APOD downregulation may contribute to OSCC progression by inhibiting the Type I interferon-JAK-STAT pathway. CONCLUSION: APOD expression is significantly reduced in OSCC, demonstrating potential as a diagnostic and prognostic biomarker. Its downregulation may facilitate disease progression through disruption of the Type I interferon-mediated JAK-STAT signaling pathway.