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

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.

Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection

“…Transmission of calcium into mitochondria depends on which ITPR isoforms are expressed at the MAM, ( 15,16 ) which varies among cell types and can change in disease states. ( 13,14,17,18 ) Therefore, we examined whether expression of each of the three ITPR isoforms was altered in YF.…”

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

“…An increased expression of ITPR3 was detected in clear renal cell carcinoma compared to the unaffected part of the kidney [81]; ITPR3 silencing affected tumor growth, in vitro as well as in vivo, providing a direct proof of the involvement of this receptor in the carcinogenesis. An increased expression of ITPR3 has been also observed in cholangiocarcinoma [82] and in colorectal cancer [83]; in both cases the expression of ITPR3 correlated with the degree of neoplasia severity [82,83].…”

Targeting Ca2+ Signaling in the Initiation, Promotion and Progression of Hepatocellular Carcinoma

“…These signaling pathways included the role of Ca 2+ in the hormonal regulation of glycolysis and one of the first observations of Ca 2+ oscillations in animal cells [ 43 , 44 ]. Likewise, intracellular Ca 2+ -signaling in cholangiocytes was well characterized (reviewed in [ 45 , 46 ]). However, much less is known about intracellular Ca 2+ -signaling in Kupffer, stellate and sinusoidal endothelial cells.…”

“…Two recent studies have shown that Ca 2+ release from the ER through InsP 3 R3 mediates the progression of both HCC and cholangiocarcinoma [ 33 , 46 ]. In hepatocytes isolated from normal human liver, expression of InsP 3 R3 was found to be very low or not detectable.…”

“…Expression of InsP 3 R3 was also found to be elevated in both hilar and intrahepatic samples from human cholangiocarcinoma liver and in cholangiocarcinoma cell lines compared to normal cholangiocytes [ 46 ]. Deletion of InsP 3 R3 from cholangiocarcinoma cell lines decreased proliferation and migration.…”