TREM2 inhibits cholangiocarcinoma progression by regulating the TGF-β/Smad2/3 signaling pathway

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor involved in the initiation and progression of multiple cancers through various pathways. However, its role in cholangiocarcinoma (CCA) remains unclear. This study aimed to elucidate the expression characteristics and functions of TREM2 in cholangiocarcinoma (CCA). First, we assessed TREM2 expression in a retrospective cohort of 55 patients with CCA using immunohistochemistry (IHC) and confirmed its localization by double immunofluorescence staining. Second, functional assays were performed to evaluate effects of TREM2 on CCA cell proliferation, migration, and invasion. Finally, mechanistic studies focused on the TGF-β/Smad2/3 pathway and epithelial-mesenchymal transition (EMT), including drug-induced activation of the TGF-β signaling pathway. In vitro assessments evaluated gemcitabine sensitivity and apoptosis, while tumorigenicity was examined using a nude mouse xenograft model. The results demonstrated that TREM2 expression in both the tumor stroma and tumor cells was inversely correlated with clinicopathological aggressiveness: high TREM2 expression was associated with a lower T stage (P = 0.004) and a lower TNM stage (P = 0.026), whereas low TREM2 expression was an independent risk factor for poorer disease-free survival. Functional studies demonstrated that TREM2 overexpression inhibited cholangiocarcinoma cell proliferation, migration, and invasion, whereas TREM2 knockdown promoted these malignant phenotypes. Mechanistic investigations revealed that TREM2 reverses the expression of epithelial-mesenchymal transition (EMT) markers by inhibiting Smad2/3 phosphorylation, and these effects can be reversed by activators of the TGF-β signaling pathway. Additionally, TREM2 enhanced gemcitabine sensitivity by lowering the gemcitabine IC50 and promoting gemcitabine-induced apoptosis. Collectively, TREM2 exerts tumor-suppressive functions in cholangiocarcinoma and enhances chemotherapy sensitivity, suggesting its potential as a therapeutic target and prognostic biomarker.