IGF2BP3-Mediated m6A Modification of OLR1 mRNA Promotes Immune Evasion in CRC via the PI3K/AKT/mTOR Pathway.
TL;DR
Functional assays confirmed that OLR1 suppressed CD8+ T-cell function and promoted tumor malignancy and IGF2BP3 stabilized OLR1 mRNA and activated the PI3K/AKT/mTOR pathway, thereby repressing the antitumor activity of CD8+ T cells and promoting immune evasion in CRC.
Abstract
Colorectal cancer (CRC) is a prevalent malignancy worldwide, with its immune evasion representing a pivotal barrier to effective immunotherapy. OLR1 is abnormally expressed in a variety of cancers, but its function in the CRC immune microenvironment and the upstream and downstream modulatory mechanisms remain unclear. Based on the TCGA-COAD data set, OLR1 was upregulated in colorectal cancer (CRC) and correlated with CD8+ T-cell infiltration. Functional assays (qRT-PCR, Western blotting, LDH, ELISA, CCK-8, CFSE, colony formation, Transwell, and flow cytometry) confirmed that OLR1 suppressed CD8+ T-cell function and promoted tumor malignancy. GSEA and inhibitor-based functional validation identified key pathways downstream of OLR1. Mechanistically, bioinformatics, RIP, RNA pull-down, MeRIP, and actinomycin D assays revealed that IGF2BP3 stabilized OLR1 mRNA. Rescue experiments further demonstrated that the IGF2BP3/OLR1 axis regulated the aforementioned pathways and CRC immune evasion. OLR1 was upregulated in CRC and negatively associated with CD8+ T-cell infiltration. Knockdown of OLR1 significantly enhanced the antitumor function of CD8+ T cells. Mechanistically, IGF2BP3 stabilized OLR1 mRNA and up-regulated its expression in an m6A modification-dependent manner, thereby activating the PI3K/AKT/mTOR pathway to inhibit the antitumor activity of CD8+ T cells. IGF2BP3 stabilized OLR1 through m6A modification and activated the PI3K/AKT/mTOR pathway, thereby repressing the antitumor activity of CD8+ T cells and promoting immune evasion in CRC.