RCN1 affects malignant progression and macrophage M2 polarization in diffuse large B-cell lymphoma

Malignant behaviors of cancer cells and immune evasion by macrophage can lead to treatment failure in diffuse large B-cell lymphoma (DLBCL). Recent studies have revealed the aberrant expression of reticulocalbin 1 (RCN1) that is associated with malignant progression of several cancers. Nevertheless, its roles in DLBCL remain unclear. In this present study, several online bioinformatics databases substantiated high expression of RCN1 in tumor samples from DLBCL patients. Furthermore, there were obvious elevation of RCN1in tumor specimens form our collected tissues and DLBCL cells. Importantly, the shorter survival outcome was observed in patients with high levels of RCN1. Intriguingly, down-regulation of RCN1 attenuated DLBCL cell viability, invasion ability and increased cancer cell apoptosis. Moreover, TIMER database revealed the correlation between RCN1 expression and tumor-infiltrating macrophages, and M2 macrophage markers in DLBCL patients. Knockdown of RCN1 suppressed cancer cell ability to induce macrophage M2-like polarization by inhibiting the percentage of CD163⁺ macrophages and expression of M2-like markers (CD163, CD204, and IL-10). Concomitantly, M2 macrophage-induced cancer cell viability and invasion was abrogated after RCN1 down-regulation. Further assay revealed that knockdown of RCN1 suppressed activation of the PI3K/AKT signaling in DLBCL cells. Notably, reactivation this pathway via its agonist 740Y-P offset the anti-tumor efficacy of RCN1 knockdown in cancer cell malignancy and macrophage polarization towards M2 phenotype. Therefore, RCN1 may contribute to the malignant progression of DLBCL by directly regulating cancer cell behavior and indirectly affecting macrophage M2-like polarization, supporting it as a promising therapeutic target against DLBCL.