Vitronectin (VTN) is a multifunctional glycoprotein that promotes cell adhesion and survival signaling through interactions with integrins. Elevated serum VTN levels have recently emerged as diagnostic and prognostic markers for hepatocellular carcinoma (HCC), yet its mechanistic role in HCC progression remains unclear. Here, we show that VTN knockdown in HCC cells has minimal effects on cell migration and viability, raising the possibility that VTN may promote tumor progression by shaping the tumor microenvironment rather than via cell-intrinsic mechanisms. To investigate this, we conducted secretome profiling after VTN knockdown in HCC cells, identifying 756 secreted proteins. Functional enrichment analysis revealed critical biological pathways and protein-protein interaction modules potentially regulated by VTN. Notably, a subset of proteins downregulated upon VTN silencing was associated with poor HCC prognosis. Using Parallel Reaction Monitoring (PRM) proteomics, we validated that the pro-tumorigenic cytokines CXCL5 and CXCL8 were significantly decreased following VTN knockdown. These findings indicate that VTN promotes expression of cytokines involved in HCC progression, implicating autocrine and paracrine mechanisms in its tumor-promoting effects.
Han et al. (2026) studied this question.