Pimwipa Ueasilamongkol1, Tanaporn Khamphaya2, Mateus T Guerra3, Michele A Rodrigues3, Dawidson A Gomes3, Yong Kong4, Wei Wei4, Dhanpat Jain5, David C Trampert3, Meenakshisundaram Ananthanarayanan3, Jesus M Banales6, Lewis R Roberts7, Farshad Farshidfar8,9, Michael H Nathanson3, Jittima Weerachayaphorn1,3. 1. Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand. 2. Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand. 3. Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT. 4. Department of Biostatistics, Yale University School of Public Health, New Haven, CT. 5. Department of Pathology, Yale University School of Medicine, New Haven, CT. 6. Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain. 7. Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN. 8. Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Canada. 9. Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada.
Abstract
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 calcium ion (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 overexpression of ITPR3 in CCA would have a mitochondrial phenotype, so this was also examined. ITPR3 normally is concentrated in a subapical region of endoplasmic reticulum (ER) in cholangiocytes, but both immunogold electron microscopy and super-resolution microscopy showed that ITPR3 in CCA cells was also 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 CCA. This contributes to malignant features, including cell proliferation and migration and enhanced mitochondrial Ca2+ signaling.
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 calcium ion (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 overexpression of ITPR3 in CCA would have a mitochondrial phenotype, so this was also examined. ITPR3 normally is concentrated in a subapical region of endoplasmic reticulum (ER) in cholangiocytes, but both immunogold electron microscopy and super-resolution microscopy showed that ITPR3 in CCA cells was also 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 CCA. This contributes to malignant features, including cell proliferation and migration and enhanced mitochondrial Ca2+ signaling.
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