title: The role of nuclear EpICD in extrahepatic cholangiocarcinoma: association with β-catenin.
abstract: 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 β-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 β-catenin in surgical specimens of extrahepatic cholangiocarcinoma (ECC) from 79 patients and focused on the relationship between nuclear expression of EpICD and β-catenin. We also examined the role of EpICD by transfecting the EpICD cDNA in cholangiocarcinoma (CC) cell lines. There was a significant correlation between the nuclear expression of EpICD and β-catenin in ECC tissues. Frequent nuclear co-localization of EpICD and β-catenin was observed in cancer cells forming the invasive front. Nuclear expression of EpICD also significantly correlated with histologic grade of tumor. 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 β-catenin and EpCAM target genes, such as c-myc and cyclin D1. Furthermore, the overexpression of EpICD significantly enhanced the migration and invasiveness of CC cells. Conversely, the inhibition of EpCAM in EpCAM-overexpressing cells by siRNA significantly decreased cell proliferation, migration and invasion. These results indicate that the spatial localization of EpICD and its mutual interaction with β-catenin may be important in ECC progression and invasion.
authors.affiliation: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Sarangerel
authors.initials: S
authors.lastname: Jachin
authors.affiliation: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Jun Sang
authors.initials: JS
authors.lastname: Bae
authors.affiliation: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Jong Jin
authors.initials: JJ
authors.lastname: Sung
authors.affiliation: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.affiliation: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Myoung Ja
authors.initials: MJ
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Dae Gohn
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Moon
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D017734:Bile Ducts, Extrahepatic / Q000473:pathology*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology; D021381:Protein Transport; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; C495270:CTNNB1 protein, human; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D051176:beta Catenin