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Introduction
Epithelial cell adhesion molecule (EpCAM) is a transmembrane protein that was first proposed to function as a homophilic cell adhesion molecule that can interfere with cadherin-mediated cell-to-cell contact (1). EpCAM is composed of a large extracellular domain (EpEx), a single transmembrane domain and a short 26-amino acid intracellular domain (EpICD) (1,2). EpCAM is frequently expressed in normal epithelial cells, and is reported to be widely upregulated in various cancers and cancer-initiating cells (3–5). The high expression of membranous EpCAM in a variety of cancers analyzed by immunohistochemistry has rendered EpCAM as an ideal immunotherapeutic target (2,3). However, results from clinical trials of EpCAM-specific monoclonal antibodies in various cancers have shown limited efficacy (6,7). The cleavage of EpEx by the protease tumor necrosis factor α-converting enzyme (TACE) and its shedding have been shown to result in the release of its intracellular domain EpICD (8). Released EpICD associates with four-and-a-half LIM domain protein 2 (FHL2), forms a nuclear complex with components of the Wnt signal pathway (β-catenin, Lef-1), and induces gene transcription, resulting in activation of oncogenic signaling (8). This proposed mechanism of regulated intramembranous proteolysis (RIP)-mediated loss of EpCAM from the cancer cell membrane and activation of oncogenic signaling via translocated nuclear EpICD might account for the restricted therapeutic efficacy of the EpCAM-targeted immunotherapy using monoclonal antibodies to target EpEx. Indeed, nuclear expression of EpICD in some types of cancer has been reported (9), and EpICD has been proposed as a new therapeutic target for cancer cells (9,10). However, little is known about the roles of EpICD in carcinogenesis and cancer progression.
β-catenin plays an important role in both adhesion and signal transduction of epithelial cells, depending on the intracellular localization. β-catenin forms adherens junctions through conjugation with α-catenin and E-cadherin at the plasma membrane. However, β-catenin can also act as a main regulator of transcription through DNA-binding proteins, such as TCF/LEF family members in the nucleus (11). Previous studies suggest that the activation of the Wnt/β-catenin signaling pathway plays an important role in human cancer invasion and metastasis (11–14). Nuclear expression of β-catenin, a hallmark of an active β-catenin-dependent Wnt pathway, was found predominantly at the invasive front of cancers (12–14).
Extrahepatic cholangiocarcinoma (ECC) arises from cholangiocytes of extrahepatic bile ducts. ECC has a...