Association of glucagon-like peptide 1 receptor and the aggressiveness of extrahepatic cholangiocarcinoma.

Previous studies demonstrated that the suppression of GLP-1R expression significantly reduced the aggressiveness of intrahepatic cholangiocarcinoma (iCCA) cells, in vitro and in vivo. However, the clinical significance of GLP-1R in extrahepatic cholangiocarcinoma (eCCA) remains unclear, although this subtype is the most common of bile duct cancer. This study thus aimed to investigate the clinicopathological significance of GLP-1R and to determine its functional roles in eCCA. GLP-1R expression in eCCA tissues was determined using immunohistochemistry. The associations between GLP-1R expression and clinicopathological characteristics and patient survival were examined using univariate analysis and the Kaplan-Meier method with the log-rank test, respectively. Roles of GLP-1R in eCCA cells were investigated using siRNA knockdown, followed by MTT proliferation assays and Transwell migration and invasion assays. Molecular mechanisms were investigated using Western blot analysis. The results showed that high GLP-1R expression was significantly associated with poor histological grading and the mucin production of eCCA (P<0.05). Knockdown of GLP-1R in eCCA cells minimally affected cell proliferation, but significantly suppressed cell migration and invasion (P<0.05). Suppressing GLP-1R expression inhibited epithelial-mesenchymal transition (EMT) in CCA cells and reduced the expression of matrix metalloproteinases 2 and 9. The common upstream regulators of EMT, namely STAT3 and Akt signaling pathways, were also suppressed after GLP-1R silencing. In conclusion, similar to iCCA, high GLP-1R expression is associated with aggressive phenotypes of eCCA. Inhibition of GLP-1R expression might then be another strategy to suppress the progression of CCA in both subtypes.