IGF2BP2 promotes lung adenocarcinoma progression by regulating LOX1 and tumor-associated neutrophils.

Abstract

Lung adenocarcinoma (LUAD) is the common form of lung cancer and is prone to distant metastasis. IGF2BP2, an m6A modification regulator, is upregulated in lung cancer tissue, but its specific role within the LUAD tumor microenvironment (TME) is unknown. We explored the role of IGF2BP2 in the progression of LUAD. IGF2BP2 expression in LUAD patient specimens and controls was evaluated through bioinformatics, Western blot, and immunohistochemistry. LUAD subcutaneous and orthotopic xenograft tumor models were established, alongside a co-culture system of tumor-associated neutrophils (TANs) and A549 cells. Functional assays assessed IGF2BP2's role under treatment with JX5, an IGF2BP2 inhibitor. Mechanistic assays explored the interaction between IGF2BP2 and LOX1 in 293T cells. IGF2BP2 was significantly upregulated in LUAD tissues, with higher expression levels predicting worse prognosis for patients (p < 0.001). In subcutaneous and orthotopic xenograft models, treatment with JX5, an IGF2BP2 inhibitor, reduced tumor size, volume, and weight (p < 0.001). JX5 also significantly reduced the concentrations of pro-inflammatory cytokines in peripheral blood (p < 0.01 and p < 0.001). Flow cytometry analysis indicated JX5 reduced CD11b+Ly6G+/CD45+ cells (TANs) in the TME (p < 0.001). Mechanistically, JX5 downregulated LOX1 expression in vivo, and co-culture experiments further demonstrated that IGF2BP2 promotes LUAD progression through LOX1-mediated regulation of TAN activity (p < 0.01 and p < 0.001). Overexpression of LOX1 reversed the inhibitory effects of JX5 on TAN infiltration, tumor cell viability, and apoptosis (p < 0.01 and p < 0.001). Additionally, RNA immunoprecipitation revealed that IGF2BP2 binds to LOX1 mRNA at its m6A modification site, stabilizing LOX1 and enhancing its function in the TME. Knockdown of IGF2BP2 accelerated LOX1 mRNA degradation, confirming its role in maintaining LOX1 stability (p < 0.01 and p < 0.001). IGF2BP2 recognizes and stabilizes LOX1 through m6A modification, contributing to TAN-mediated LUAD progression. Overall, these findings offer new insights into LUAD progression and demonstrate that IGF2BP2 is a key regulator that promotes tumor advancement, highlighting the IGF2BP2-LOX1 axis as a potential therapeutic target for LUAD.