Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.
Hepatology. 2020 Feb;71(2):583-599. doi: 10.1002/hep.30839. Epub 2019 Aug 19.
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 (Ca ) 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 Ca 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 Ca signaling.
胆管癌（CCA）是肝脏中第二常见的恶性肿瘤。它的预后较差，部分原因是其发病机制尚不清楚。三型肌醇 1,4,5-三磷酸受体（ITPR3）是胆管细胞中主要的细胞内钙离子（Ca ）释放通道，其表达增加与其他类型组织的恶性肿瘤的发病机制有关，因此我们研究了其在 CCA 中的作用。ITPR3 在肝门部和肝内 CCA 样本以及 CCA 细胞系中的表达均增加。CCA 细胞中 ITPR3 的缺失会损害增殖和细胞迁移。生物信息学分析表明，CCA 中 ITPR3 的过表达会具有线粒体表型，因此也对此进行了检查。ITPR3 通常在胆管细胞的内质网（ER）的亚顶点区域集中，但免疫金电子显微镜和超分辨率显微镜均显示 CCA 细胞中的 ITPR3 也存在于与线粒体密切相关的 ER 区域。从这些细胞中删除 ITPR3 会损害线粒体 Ca 信号转导并导致细胞死亡。结论：胆管细胞中 ITPR3 的表达在 CCA 中增强。这有助于恶性特征，包括细胞增殖和迁移以及增强的线粒体 Ca 信号转导。
