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Hepatology. 2019 Jun 28. doi: 10.1002/hep.30839. [Epub ahead of print]

Type 3 inositol 1,4,5-trisphosphate receptor is increased and enhances malignant properties in cholangiocarcinoma.

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Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.
Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut, USA.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain.
Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Department of Oncology, Cumming School of Medicine, University of Calgary, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada.


Cholangiocarcinoma (CCA) is the second most common malignancy arising in the liver. It carries a poor prognosis, in part because its pathogenesis is not well understood. The type 3 inositol 1,4,5-trisphosphate receptor (ITPR3) is the principal intracellular Ca2+ release channel in cholangiocytes and its increased expression has been related to the pathogenesis of malignancies in other types of tissues, so we investigated its role in CCA. ITPR3 expression was increased in both hilar and intrahepatic CCA samples as well as in CCA cell lines. Deletion of ITPR3 from CCA cells impaired proliferation and cell migration. A bioinformatic analysis suggested that over-expression of ITPR3 in CCA would have a mitochondrial phenotype, so this also was examined. ITPR3 normally is concentrated in a sub-apical region of endoplasmic reticulum (ER) in cholangiocytes, but both immunogold electron microscopy and super-resolution microscopy showed that ITPR3 in CCA cells also was in regions of ER in close association with mitochondria. Deletion of ITPR3 from these cells impaired mitochondrial Ca2+ signaling and led to cell death. CONCLUSION: ITPR3 expression in cholangiocytes becomes enhanced in cholangiocarcinoma. This contributes to malignant features, including cell proliferation and migration and enhanced mitochondrial Ca2+ signaling. This article is protected by copyright. All rights reserved.


Apoptosis; Calcium signaling; Cell proliferation; Cholangiocyte; Mitochondria


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