MYBL2 promotes malignant phenotypes and M2-like macrophage polarization through CCL2 in non-small cell lung cancer.

Abstract

Hub genes associated with non-small cell lung cancer (NSCLC) were identified through bioinformatics screening. In vitro experiments analyzed the potential mechanisms by which these genes regulate tumor malignant phenotypes and macrophage polarization. Differentially expressed genes were identified from The Cancer Genome Atlas (TCGA)-NSCLC and GSE32175 datasets, followed by protein-protein interaction (PPI) network analysis to screen hub genes. The effects of MYB Proto-Oncogene Like 2 (MYBL2) on NSCLC progression and macrophage polarization were evaluated using in vitro models. The regulatory relationship between MYBL2 and C-C motif chemokine ligand 2 (CCL2) was investigated by Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, and rescue experiments were performed to validate the role of the MYBL2-CCL2 axis. Bioinformatics screening identified BUB1B, CDCA2 and MYBL2 as key hub genes with high expression in NSCLC, among which MYBL2 was significantly upregulated in NSCLC cells. Functional experiments confirmed that MYBL2 silencing markedly inhibited the malignant proliferation, migration and invasion of NSCLC cells. Tumor cell MYBL2 knockdown effectively reversed M2-like polarization and promoted M1-like polarization in the co-culture system. Mechanistically, MYBL2 directly bound to the CCL2 promoter region to enhance CCL2 transcriptional activity and upregulate CCL2 expression in NSCLC cells. Exogenous CCL2 supplementation significantly rescued the inhibitory effect of MYBL2 knockdown on macrophage M2-like polarization, verifying the mediating role of CCL2 in this regulatory axis. MYBL2 is strongly expressed in NSCLC cells and is associated with enhanced malignant phenotypes. It may affect macrophage M2-like polarization by upregulating CCL2, thus participating in NSCLC immune microenvironment remodeling.