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Cholangiocarcinoma (CHOL) is an aggressive gastrointestinal carcinoma, characterized by its rapid progression and the absence of effective therapeutic biomarkers. Although recent studies have implicated S100A12 in tumor formation, its specific functions in CHOL development have been insufficiently explored. We conducted an integrative multi-omics study combining Mendelian Randomization (MR) and bioinformatics. The MR approach was employed to investigate causal relationships between cytokines, immune cells, and CHOL risk. Bioinformatics analysis utilizing data from TCGA and GTEx database assessed S100A12 expression in CHOL tissues, functional enrichment, and correlations with immune infiltration as well as immune checkpoint molecules. Experimental validation was conducted using siRNA-mediated S100A12 knockdown in CHOL cell lines, followed by functional assays including proliferation, invasion, and migration. S100A12 exhibited a significant causal association with CHOL risk. Bioinformatics analysis further confirmed that S100A12 is significantly upregulated in cholangiocarcinoma and associated with poor prognosis. The high S100A12 expression group displayed a distinct immune cell infiltration pattern characterized by reduced regulatory T cells and increased M0, M2 macrophages, and neutrophils. Furthermore, S100A12 expression correlated with a series of co-stimulatory or co-inhibitory immune checkpoint molecules. In vitro studies validated that S100A12 enhances proliferation, invasion, and migration capabilities in CHOL cell lines RBE and HuccT1 while simultaneously suppressing apoptosis. The study identified S100A12 as a potential biomarker and therapeutic target for CHOL, paving the way for improved management of this aggressive cancer.