Urine proteomics-based analysis identifies CHI3L1 as an immune marker and potential therapeutic target for bladder cancer.

BACKGROUND: Bladder cancer (BCa) is a prevalent malignancy characterized by a poor prognosis. Numerous studies have increasingly recognized the role of M2 macrophages in cancer progression. Consequently, our objective is to investigate hub genes in BCa associated with M2 macrophages, assessing their prognostic significance and exploring potential regulatory mechanisms.

METHODS: We performed a comprehensive bioinformatics analysis using data from urine proteomics, the Gene Expression Omnibus (GEO) database, and The Cancer Genome Atlas (TCGA) database, in conjunction with machine learning methods such as LASSO and SVM to identify intersections of differentially expressed genes (DEGs). Subsequently, the role of hub genes in BCa was validated in vitro and in vivo using CCK-8 assay, wound healing assay, immunofluorescence assay, transwell assay, immunohistochemistry, and xenograft tumor model. Finally, we investigated the correlation between hub genes and M2 macrophage immune infiltration using the TIMER database.

RESULTS: Chitinase 3 like 1 (CHI3L1) emerged as a pivotal gene linked to M2 macrophages in BCa. Notably, CHI3L1 was associated with a poor prognosis for BCa, with elevated expression correlating to more advanced histologic and pathologic stages in BCa patients. The findings suggest that inhibiting CHI3L1 can effectively impede the proliferation, migration, and invasion of BCa cells and synergistically increase the inhibitory effect of gemcitabine (GEM) on cell activity. Meanwhile, the downregulation of CHI3L1 was accompanied by inhibition of the PI3K-AKT signaling pathway. Additionally, CHI3L1 demonstrated a significant association with M2 macrophage infiltration in the BCa tumor microenvironment (TME).

CONCLUSIONS: The present study suggests that CHI3L1 may promote bladder cancer progression through the PI3K-Akt signaling pathway and is associated with M2 macrophage infiltration.