MCM10, regulated by METTL3/ YTHDF1-mediated m6A modification, contributes to colorectal cancer progression through induction of M2 macrophage polarization

Abstract Colorectal cancer (CRC) remains a major contributor to cancer-related mortality worldwide. Although minichromosome maintenance protein 10 (MCM10) is known for its role in DNA replication, its involvement in CRC progression has not been fully elucidated. To identify key oncogenic drivers, RNA sequencing was performed on seven paired CRC and adjacent normal tissues, revealing significant upregulation of MCM10 (Log2FC = 2.359, P = 0.003). Public GEO datasets (GSE240623, GSE200427) further confirmed MCM10 overexpression in CRC tissues. This finding was validated in 40 paired clinical samples using qPCR and Western blotting. Prognostic relevance was assessed using hazard ratio (HR). Functional assays in vitro and in vivo were conducted to assess the effects of MCM10 on proliferation, migration, invasion, and M2 macrophage polarization. The m6A modification of MCM10 mRNA was evaluated through METTL3 and YTHDF1 interaction analysis in HCT116 cells. MCM10 was significantly upregulated in CRC tissues and associated with poor prognosis (HR = 1.54, P = 0.00077). MCM10 overexpression promoted CRC cell proliferation and invasion and was correlated with elevated M2 macrophage infiltration in tumor xenografts (6.16 ± 0.85% vs. 11.7 ± 1.13%, P < 0.05). Conditioned media from MCM10-overexpressing cells enhanced THP-1 macrophage polarization by increasing secretion of CCL2, CCL5, and IL10. Mechanistically, METTL3-mediated m6A modification stabilized MCM10 mRNA in a YTHDF1-dependent manner. MCM10 is aberrantly overexpressed in CRC and linked to worse clinical outcomes. Its oncogenic effects involve METTL3/YTHDF1-mediated mRNA stabilization and enhanced M2 macrophage polarization, suggesting a potential role in immune microenvironment modulation.