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.
Post‐menopausal condition reduces not only bone mass but also skin nerve innervation. Estrogen may play roles in the regulation of nerve integrity in bone. Effects on sensory nerve integrity relevant to osteoporosis by estrogen in six‐month‐old sham and ovariectomized rats (OVX) with or without daily subcutaneously supplementation of 17β‐estradiol (E2, 1, 5 or 15 μg/kg BW) were examined. After 3 months, dual‐energy x‐ray absorptiometry was performed at left femur for bone mass density (BMD) and immunoreactivity (ir) of the neuronal and sensory neurotransmitter marker antibodies, anti‐PGP 9.5, anti‐calcitonin gene related peptides (CGRP) and anti‐substance P (SP) antibody at right femur. OVX rats without E2 supplement showed the lowest BMD at the distal femur, but not the proximal femur. The bone loss in the distal femur was in parallel with decreased PGP‐9.5, CGRP and SP‐ir at the distal femur of the same subjects whereas the up‐regulation of CGRP‐ir was indicated at the proximal femur. Daily E2 injection prevented these changes. The results indicated the presence of bone sensory nerve which was regulated by estrogen. The protection of bone loss induced by estrogen depletion may require the up‐regulation of nerve containing CGRP. This work was supported by Graduate school, Chulalongkorn University.
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