CD109 Expression in Tumor and Stromal Cells Serves as a Prognostic Biomarker for Tumor Progression and Outcome in Gallbladder Adenocarcinoma

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is upregulated in various human cancers and exhibits tumor-promoting effects. In this study, we investigated the role of CD109 in gallbladder adenocarcinoma (GBAC). CD109 expression in 77 resected GBAC samples was immunohistochemically evaluated. CD109 expression in tumor cells correlated with TNM stage, N factor, histological grade, lymphatic invasion, and perineural invasion and was associated with reduced disease-free survival (DFS) and overall survival (OS). Stromal CD109 expression was detected in several cases, similar to that of α-SMA and FAP, suggesting its presence in cancer-associated fibroblasts. Stromal expression was also correlated with TNM stage, N factor, perineural invasion, and reduced DFS. Combined analysis of CD109 expression in tumor and stromal cells further stratified patients by prognosis. CD109 overexpression in GBAC cell lines induced the expression of the epithelial-to-mesenchymal transition (EMT) markers. Analyses using a public database revealed the association between CD109 and EMT-related gene expression in biliary tract cancer cell lines. Moreover, CD109 depletion promoted enhanced transforming growth factor-β1/Smad3 signaling and attenuated epidermal growth factor/AKT signaling in GBAC cells in a cell type-dependent manner. Collectively, these findings suggest that CD109 may serve as a prognostic biomarker of tumor progression and outcome in GBAC.