Type 3 Inositol 1,4,5-Trisphosphate Receptor Is Increased and Enhances Malignant Properties in Cholangiocarcinoma

Pimwipa Ueasilamongkol, Tanaporn Khamphaya, Mateus T. Guerra, Michele A. Rodrigues, Dawidson A. Gomes, Yong Kong, Wei Wei, Dhanpat Jain, David C. Trampert, Meenakshisundaram Ananthanarayanan, Jesus M. Banales, Lewis R. Roberts, Farshad Farshidfar, Michael H. Nathanson, Jittima Weerachayaphorn

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)583-599
Number of pages17
JournalHepatology
Volume71
Issue number2
DOIs
StatePublished - Feb 1 2020

ASJC Scopus subject areas

  • Hepatology

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