DBF4B promotes hepatocellular carcinoma progression by regulating CCNA2 and PSMD11 expression

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy characterized by unfavorable clinical outcomes. Identifying novel biomarkers and therapeutic targets is essential for advancing HCC management. Although DBF4 zinc finger B (DBF4B) has been associated with the progression of various cancers, its specific role in HCC remains poorly understood. The expression pattern of DBF4B in HCC tissues was analyzed using the Gene Expression Omnibus (GEO) database. Prognostic analysis was performed using The Cancer Genome Atlas (TCGA) database, and the prognostic value of DBF4B was evaluated through Kaplan-Meier survival analysis and nomogram construction. Subsequently, the expression level and prognostic significance of DBF4B were validated using clinical tissue microarray (TMA) samples. In vitro functional experiments were conducted to investigate the effects of DBF4B knockdown on HCC cell proliferation and migration. Bioinformatics enrichment analysis, qRT-PCR and Western blotting were employed to explore the downstream molecular mechanisms of DBF4B. Rescue experiments were performed to validate the downstream mechanism, and a subcutaneous xenograft model in nude mice was established to evaluate the impact of DBF4B silencing on tumor growth. DBF4B expression was upregulated in HCC tissues and cell lines. High DBF4B expression was closely associated with shorter overall survival (OS) and progression-free survival (PFS) in HCC patients, and served as an independent prognostic factor. Functional experiments demonstrated that silencing DBF4B markedly suppressed the proliferative and migratory capabilities of HCC cells. Mechanistically, DBF4B positively regulated the expression of cyclin A2 (CCNA2) and proteasome 26 S subunit non-ATPase 11 (PSMD11), which are key regulators of cell cycle progression. Of these two molecules, CCNA2 was prioritized for subsequent functional rescue studies. Overexpression of CCNA2 effectively restored the proliferative and migratory capacities impaired by DBF4B silencing. Moreover, in vivo xenograft models showed that DBF4B silencing substantially inhibited tumor growth, as reflected by diminished tumor volume and weight, along with downregulation of the proliferation marker Ki67. DBF4B acts as an oncogene in HCC by promoting cell proliferation and migration through regulating CCNA2 and PSMD11 expression. Thus, it holds promise as both a prognostic biomarker and a novel therapeutic target for HCC.