Integrative multi-omics and experimental validation reveal the oncogenic role of DDX52 in liver hepatocellular carcinoma.

BACKGROUND

The DExD/H-box (DDX) helicase family plays critical roles in RNA metabolism and has been implicated in tumorigenesis. However, the pan-cancer activities and prognostic potential of DDX52, especially in liver hepatocellular carcinoma (LIHC), are largely unknown.

METHODS

We comprehensively analyzed DDX52 across pan-cancer using TCGA, GEO, HPA, and SpatialTME databases, assessing its differential expression, prognosis, genetic alterations, Tumor Mutational Burden (TMB), Microsatellite Instability (MSI), and immune microenvironment features. In LIHC, we performed functional enrichment, PPI network, single-cell sequencing, and drug sensitivity analyses. Molecular docking explore potential small-molecule inhibitors of DDX52. Finally, we validated DDX52 expression and function in LIHC.

RESULTS

DDX52 mRNA and protein expression were significantly upregulated in multiple malignancies, including LIHC. Elevated DDX52 expression correlated with poor prognosis in LIHC. Genetic analysis revealed frequent copy number variations (CNV) and single-nucleotide variants (SNV) of DDX52, with significant positive correlations between DDX52 expression and both TMB and MSI across numerous cancer types. DDX52 expression was also significantly associated with immune cell infiltration, immune checkpoint molecules. In LIHC, DDX52 was predominantly expressed in B cells, proliferating T cells, malignant cells, and monocytes/macrophages. Functional enrichment analysis indicated DDX52 involvement in metabolic processes, histone modification, cell cycle regulation, and oncogenic signaling pathways. Pharmacologically, high DDX52 expression correlated with reduced drug sensitivity. Experimentally, DDX52 silencing significantly inhibited proliferation, colony formation, migration, and invasion in HepG2 and MHCC-97H cells.

CONCLUSIONS

Our integrative analyses and experimental validation suggest that DDX52 is a potential prognostic biomarker and therapeutic target in LIHC. Its associations with immune features and multiple cancer-related pathways provide hypotheses for future mechanistic investigation.