Prognostic Significance of HMGA1 in Hepatocellular Carcinoma: Implications for Tumor Progression and Targeted Therapy.

[BACKGROUND] High mobility group A1 (HMGA1) has emerged as a key oncogenic factor in various cancers, but its specific role in liver hepatocellular carcinoma (LIHC) remains incompletely understood. This study aimed to investigate the expression pattern, biological functions, immune associations, clinical relevance, and therapeutic potential of HMGA1 in LIHC.

[METHODS] We conducted a multi-omics analysis integrating transcriptomic, proteomic, and clinical data from TCGA, CPTAC, and HPA databases. Functional enrichment, immune infiltration profiling, and survival analyses were performed. assays, including CCK-8, colony formation, β-galactosidase staining, and wound healing, were used to validate HMGA1's biological functions in LIHC cells.

[RESULTS] HMGA1 was significantly overexpressed in LIHC at both mRNA and protein levels (<0.001). High HMGA1 expression correlated with advanced pathological stage, metastasis, and elevated AFP levels (all <0.001). Kaplan-Meier analysis revealed that elevated HMGA1 predicted poor overall survival (OS) (HR=1.83, 95% CI: 1.12-2.99, =0.014), disease-specific survival (DSS) (HR=2.12, 95% CI: 1.33-3.35, =0.002), and progression-free interval (PFI) (HR=1.68, 95% CI: 1.14-2.48, =0.009). Multivariate Cox analysis confirmed HMGA1 as an independent prognostic factor for OS (HR=1.75, 95% CI: 1.11-2.76, =0.016). A nomogram incorporating HMGA1 and clinicopathological variables showed good predictive performance with a 3-year AUC of 0.723. Functionally, HMGA1 knockdown suppressed LIHC cell proliferation (38.9% reduction in HepG2 and 46.0% in Huh-7 at 48h), migration (44-59% inhibition at 24h), and colony formation (41.8-44.2% reduction), while significantly inducing cellular senescence (3.4-3.5-fold increase in β-gal+cells, <0.001). GSEA and immune analysis indicated that HMGA1 may promote immune evasion and senescence bypass.

[CONCLUSION] HMGA1 serves as a robust prognostic biomarker and functional driver of malignant progression in LIHC. Its integration into prognostic models may enhance risk stratification and guide personalized therapeutic strategies. Nevertheless, further validation and prospective clinical studies are required to establish its translational applicability.