Spexin expression in the human bile duct and perihilar cholangiocarcinoma

Abstract

The bile duct transports bile fluid from the liver to the gallbladder and small intestine. It contains bioactive peptides, including galanin (GAL) and its receptors (GAL_1–3-R). Spexin (SPX), a member of the GAL peptide family, activates GAL₂-R and GAL₃-R. Its expression in perihilar bile ducts or in perihilar cholangiocarcinoma (pCCA), the most common biliary cancer, is largely unknown. This study investigated SPX expression in healthy, cholestatic, and malignant bile duct tissues. Immunohistochemistry was used to evaluate SPX in healthy (n = 4), peritumoral (PIT) (n = 23) and pCCA (n = 34) tissues. Score values of SPX expression were calculated and statistically analyzed. In healthy and PIT tissues with or without cholestasis, SPX expression was predominantly observed in cholangiocytes and nerve fibers. In pCCA, tumor cells also expressed SPX. SPX levels were similar across healthy, peritumoral, and cholangiocytes/tumor cells. In a small pCCA patient cohort (n = 19), SPX expression did not correlate with tumor grade or patient survival (p = 0.0838). The substantial expression of SPX in cholangiocytes and nerve fibers in the bile duct indicates that SPX contributes via galaninergic signaling to gall bladder function. The presence of SPX in submucosal nerve fibers suggests a neuromodulatory role, possibly involving bile duct motility. SPX expression did not correlate with survival in pCCA, whereas previous findings on GAL suggest a prognostic value. This highlights the need for joint studies of SPX and GAL in larger cohorts.