MBNL3 regulates tumor progression and metastasis in cholangiocarcinoma and serves as a prognostic biomarker.

Cholangiocarcinoma (CHOL) is a highly fatal malignancy originating from the bile ducts, with most patients diagnosed at an advanced stage, limiting treatment options. This study explores the role of Muscleblind-like 3 (MBNL3), a conserved RNA-binding protein, in CHOL progression, particularly its involvement in metastasis and immune microenvironment regulation. Using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we investigated MBNL3 expression and its correlation with patient prognosis. High MBNL3 expression was associated with significantly better overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), and disease-free interval (DFI) in CHOL patients. Functional analysis revealed that MBNL3 modulates epithelial-mesenchymal transition (EMT) and interacts with critical pathways, including focal adhesion, collagen signaling, and TNF signaling. Additionally, MBNL3 influences immune cell infiltration, with high expression linked to increased macrophage and Th17 cell presence, suggesting potential roles in immune response modulation. Experimental validation confirmed that silencing MBNL3 promotes EMT, enhances tumor cell migration and invasion, and increases metastasis in vivo. Furthermore, genetic analyses highlighted the impact of MBNL3 mutations and methylation on CHOL progression, identifying potential targets for immunotherapy. This is the first study to investigate MBNL3's role in CHOL, positioning it as a prognostic biomarker and a promising therapeutic target for improving outcomes in CHOL patients. Further research is needed to elucidate the molecular mechanisms underlying MBNL3's regulation of tumor metastasis and the immune microenvironment.