RESUMO
In recent years, CC chemokine receptor 2 (CCR2) has been found to be involved in tumor growth, angiogenesis, epithelial mesenchymal transition, metastasis, and immune escape. CCR2 overexpression was first identified as a poor prognostic predictor in diffuse large B-cell lymphoma (DLBCL) in our published article, but the mechanisms involved remain unknown. In this work, we collected data from another 138 patients with DLBCL data and verified the CCR2 expression level and its relationship to clinicopathological characteristics. Furthermore, we explored the possible mechanisms via in vitro and in vivo experiments. We showed that CCR2 overexpression was an independent prognostic marker and predicted shorter overall survival (OS) and progression-free survival (PFS) in patients with DLBCL. Blockade of CCR2 expression with a CCR2 antagonist inhibited tumor cell proliferation, migration, and anti-apoptosis ability in vitro by affecting the PI3K/Akt signaling pathway and the p38 MAPK signaling pathway. Furthermore, administration of a CCR2 antagonist decreased tumor growth and dissemination of DLBCL cells and increased survival time in the xenograft model. Our study demonstrates that CCR2 expression plays an important role in the development of DLBCL by stimulating cell proliferation, migration, and anti-apoptosis. Therefore, the inhibition of CCR2 may be a potential target for anticancer therapy in DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B , Receptores CCR2 , Humanos , Receptores CCR2/genética , Receptores CCR2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Linfoma Difuso de Grandes Células B/metabolismo , Prognóstico , Processos NeoplásicosRESUMO
Since the approval by the Food and Drug Administration (FDA), ferumoxytol and other iron oxide nanoparticles (IONs) have been widely used as iron supplements for patients with iron deficiency. Meanwhile, IONs have also been used as contrast agents in magnetic resonance imaging and as drug carriers. Importantly, IONs have demonstrated a significant inhibitory effect on the growth of tumors, including hematopoietic and lymphoid tumors, such as leukemia. In this study, we further demonstrated the effect of IONs on inhibiting the growth of diffuse large B-cell lymphoma (DLBCL) cells by enhancing ferroptosis-mediated cell death. IONs treatment caused an accumulation of intracellular ferrous iron and the onset of lipid peroxidation in DLBCL cells as well as the suppressed expression of anti-ferroptosis protein Glutathione Peroxidase 4 (GPX4), thereby leading to increased ferroptosis. Mechanistically, IONs increased cellular lipid peroxidation through the generation of ROS via the Fenton reaction and regulating the iron metabolism-related proteins, such as ferroportin (FPN) and transferrin receptor (TFR), which elevated the intracellular labile iron pool (LIP). Hence, our findings suggest the potential therapeutic effect of IONs on the treatment of patients with DLBCL.