Promotion of Melanoma Progression through MCM4-Induced Immune Suppression and Polarization of Macrophages by Carcinogenic Exosomes.

Abstract

Objective: This study aims to provide a comprehensive understanding of the crucial role of MCM4 in melanoma progression regarding the regulatory communication between macrophages and cancer cells mediated by extracellular vesicles.

Methods: Initially, a preliminary analysis was conducted using the Tumor Immune Estimation Resource (TIMER) database. Subsequently, the role of MCM4 knockdown on the polarization of THP- 1 and RAW264.7 macrophages was observed. Finally, the biological functionalities of exosomes derived from A375 cells overexpressing MCM4 on normal melanocytes (HEM-L) were explored.

Results: On the one hand, MCM4 knockdown resulted in the upregulation of M1 macrophage markers and downregulation of M2 macrophage markers, indicating that MCM4 could facilitate polarization of macrophages toward the M2 phenotype and suggesting its oncogenic potential. On the other hand, MCM4 overexpression in melanocytes increased the secretion of exosomes, enhancing the proliferation, clonogenic, and DNA synthesis abilities of normal melanocytes. In addition, MCM4 overexpression-induced secretion of exosomes promoted the migration and invasion capabilities of normal melanocytes.

Conclusion: Exosomes secreted by MCM4-overexpressed melanocytes could stimulate their proliferation, migration, and invasion abilities. MCM4 promoted M2 polarization of macrophages, indicating its crucial role in tumor microenvironment formation and thereby facilitating tumor development.