Original ArticleClaudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer

•Bile duct neoplasia-related claudin-18 expression is induced by EGFR/ERK signaling.•Claudin-18 expression is involved in cell proliferation, invasion and tumorigenicity in vivo.•Extracellular loop of claudin-18-specific antibody has inhibitory effect for cell proliferation.•Enhanced claudin-18 expression activates ERK1/2, suggesting a positive feedback loop.

Our recent work revealed that elevated expression of claudin-18 is involved in bile duct neoplasia. In the present study, we found that wound generation of a cell sheet de novo induced claudin-18 expression in its leading edge, coincident with high mitotic activity. We also found that the suppression of claudin-18 expression significantly reduced cell growth and invasiveness of bile duct cancer cell lines and tumorigenicity in vivo. In addition, an antibody specific to an extracellular loop of claudin-18 showed similar effects on the cells such as cell proliferation. Interestingly, treatment with epidermal growth factor (EGF) and overexpression of RAS oncogene induced claudin-18 expression by activation of extracellular signal-related kinase (ERK)1/2. Furthermore, enhanced claudin-18 expression activated ERK1/2. These findings provide evidence for an oncogenic property of claudin-18 in bile duct carcinoma cells via modulation of EGFR/ERK signaling, indicating that claudin-18 is a possible therapeutic target for this malignancy.