Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer. (10th September 2017)

• Record Type: Journal Article
• Authors: Takasawa, Kumi; Takasawa, Akira; Osanai, Makoto; Aoyama, Tomoyuki; Ono, Yusuke; Kono, Tsuyoshi; Hirohashi, Yoshihiko; Murata, Masaki; Sawada, Norimasa
• Is Part Of: Cancer letters. Volume 403(2017)
• Page Start: 66
• Page End: 73
• Publication Date: 2017-09-10
• Subjects: Claudin-18 -- Bile duct cancer -- EGFR/ERK signaling -- Therapeutic target -- Tight junction protein; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.05.033
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: 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.