The role of nuclear EpICD in extrahepatic cholangiocarcinoma: association with beta-catenin

After intramembranous proteolysis-mediated loss of the extracellular domain of the epithelial cell adhesion molecule (EpEx) and release of an intracellular domain (EpICD) into the cytoplasm, EpICD sequentially associates with FHL2 to form a nuclear complex with beta-catenin and Lef-1. This association induces gene transcription involved in the activation of the oncogenic potential of epithelial cell adhesion molecule (EpCAM). We examined the localization and expression of EpEx, EpICD and beta-catenin in surgical specimens of extrahepatic cholangiocarcinoma (ECC) from 79 patients. There was a significant correlation between the nuclear expression of EpICD and beta-catenin in ECC tissues. Frequent nuclear co-localization of EpICD and beta-cate-nin was observed in cancer cells forming the invasive front. Forced overexpression of EpICD in the CC cells significantly increased the cell growth and proliferation. The overexpression of EpICD in the CC cells also increased the expression levels of the active form of beta-catenin and EpCAM target genes. Furthermore, the over-expression of EpICD significantly enhanced the migration and invasiveness of CC cells. Conversely, inhibition of EpCAM by siRNA significantly decreased the CC cell proliferation, migration and invasion. These results indicate that spatial localization of EpICD and its mutual interaction with beta-catenin may be important in ECC progression and invasion.