CHI3L1: a key driver in gastritis-to-cancer transformation.

Abstract

Background: Gastric cancer, recognized as one of the most lethal malignancies globally, progresses through a complex, multi-stage development. Elucidating the pathogenic mechanisms behind gastric carcinogenesis and identifying early diagnostic biomarkers are pivotal for decreasing the prevalence of gastric cancer.

Methods: Using datasets on gastric cancer and its transformation from gastritis, we employed machine learning to create an early diagnostic model, identifying key genes and evaluating accuracy. We prioritized genes in the gastritis-to-cancer progression, identifying a central driver gene. Pathway analysis revealed its transformation role. Tissue microarrays and rat models validated the driver genes and networks, confirmed in cell and organoid models. We also identified cell types secreting CHI3L1 using single-cell RNA sequencing and multiplex immunohistochemistry, exploring their prognostic significance.

Results: We identified 12 driver genes potentially involved in the gastritis-to-cancer transformation, with CHI3L1, MMP12, CXCL6, IDO1, and CCL20 emerging as the top five genes via a early gastric cancer diagnostic model. CHI3L1 was pinpointed as the central driver across the gastritis-to-cancer spectrum, with its upregulation, along with CD44, β-catenin, and c-Myc, noted in gastric precancerous lesions. In vitro and organoid studies revealed CHI3L1's role in activating the CD44-β-catenin pathway to induce malignancy. Furthermore, our findings indicate that fibroblasts and dendritic cells are the principal sources of CHI3L1 secretion, a factor that is associated with poor prognosis in gastric cancer.

Conclusions: This study highlights CHI3L1 as a key gene driving the progression from gastritis to gastric cancer, primarily by activating the CD44-β-catenin pathway, which enhances malignant cell traits. CHI3L1 is mainly secreted by fibroblasts and dendritic cells, and its high levels are linked to poor gastric cancer prognosis.