Different roles of S100P overexpression in intrahepatic cholangiocarcinoma; Carcinogenesis of perihilar type and aggressive behavior of peripheral type Running title: S100P expression in intrahepatic cholangiocarcinoma

S100P is expressed in several kinds of malignant tumors. Intracellular S100P interacts with ezrin, and extracellular S100P activates the receptor for advanced glycation end-products (RAGE). However, little is known about the biological significance of S100P and related protein in cholangiocarcinoma. Biliary intraepithelial neoplasia (BilIN) is a precursor lesion of hilar or perihilar cholangiocarcinoma. We examined S100P, ezrin, and RAGE expression in 39 biliary intraepithelial neoplasia (BilIN) and 110 intrahepatic cholangiocarcinoma (ICC) cases, and analyzed its relation with clinicopathological factors and outcomes. S100P expression increased from reactive epithelium to low-grade BilIN to high-grade BilIN. S100P and ezrin expression rates in perihilar type ICC were higher than those in peripheral type ICC (p<0.0001, p=0.0008, respectively). S100P nuclear expression in peripheral type ICC was significantly correlated with vascular invasion (p=0.0209), lymphatic invasion (p=0.0003), and lymph node metastasis (p=0.003). S100P and ezrin expression was significantly correlated. S100P-positive and ezrin-positive cases indicate shorter survival in survival analysis of peripheral type (p=0.001, p=0.0728, respectively). Our results suggest that S100P-ezrin signaling have different roles of carcinogenesis of perihilar ICC and aggressive course of peripheral ICC.