Extracellular ubiquitin inhibits the apoptosis of hepatoma cells via the involvement of macrophages

BACKGROUND: Blood transfusion is a vital treatment for cancer patients, but some studies have proved that there is an association between transfusion and the risk of cancer recurrence. Storage time influences the quality of red blood cells (RBCs), and the transfusion of aged RBCs can result in hepatocellular carcinoma (HCC) recurrence, which could be related to the ubiquitin (Ub) released by aged RBCs. In this study, we explored the effect of eUb on the biological characteristics of hepatoma cells. METHODS: We checked the proliferation and apoptosis of hepatoma cells (MHCC-97H and HepG2.2.15) by CCK-8, colony formation assay, flow cytometry and Western blot. THP-1-derived macrophages were used in this study, and the co-culturing of hepatoma cells with macrophages was initiated with Transwell inserts. We also measured the secretion of macrophages through ELISA. RESULTS: eUb did not directly influence the proliferation and apoptosis of hepatoma cells. However, the Akt/mTOR signaling pathway in hepatoma cells was activated, and the apoptosis of hepatoma cells was inhibited significantly after they were co-cultured with the macrophages pretreated with eUb. In addition, we confirmed that eUb modulated the phenotype and secretion function of macrophages. CONCLUSIONS: Extracellular Ub repressed the apoptosis of hepatoma cells via the involvement of macrophages, which might affect the local tumor microenvironment and display pro-tumor effect.