Abstract
The small liver fluke Clonorchis sinensis causes hepatobiliary ductal infections in humans. Clonorchiasis is characterized histopathologically by ductal dysplasia, hyperplasia and metaplasia, which closely resembles cholangiocarcinoma (CCA). The disruption of programmed cell death is critical for malignant transformation, while molecular events underlying these phenomena have poorly been understood in clonorchiasis-related CCA tumorigenesis. We incorporated recombinant C. sinensis omega-class glutathione transferase (rCsGSTo) 1 or 2 into human intrahepatic biliary epithelial cells (HIBECs) and analyzed pathophysiological alterations of HIBECs upon the application of oxidative stress. rCsGSTos partially but significantly rescued HIBECs from cell death by inhibiting oxidative stress-induced apoptosis (p < 0.01). rCsGSTos modulated transcriptional levels of numerous genes. We analyzed 13 genes involved in programmed cell death (the upregulation of five antiapoptotic and two apoptotic genes, and the downregulation of one antiapoptotic and five apoptotic genes) and 11 genes associated with cell differentiation (the increase in seven and decrease in four genes) that showed significant modifications (p < 0.05). The induction profiles of the mRNA and proteins of these differentially regulated genes correlated well with each other, and mostly favored apoptotic suppression and/or cell differentiation. We detected increased active, phosphorylated forms of Src, PI3K/Akt, NF-κB p65, MKK3/6 and p38 MAPK, but not JNK and ERK1/2. CsGSTos were localized in the C. sinensis-infected rat cholangiocytes, where cytokeratin 19 was distributed. Our results demonstrated that CsGSTos excreted to the biliary lumen are internalized and accumulated in the host cholangiocytes. When cholangiocytes underwent oxidative stressful condition, CsGSTos appeared to be critically involved in both antiapoptotic process and the differentiation of host cholangiocytes through the regulation of target genes following the activation of responsible signal molecules.
Highlights
We identified 13 genes involved in programmed cell death which were modified as a part of the oxidative stress response; seven antiapoptotic genes, i.e., angiopoietin-like 4 (ANGPTL4), B-cell lymphoma
CsGSTos assimilated within host cholangiocytes appear to augment anti-apoptosis through the increase in the active, phosphorylated forms of Src, PI3K/Akt and NF-κB p65 and the subsequent modulation of several genes involved in programmed cell death
On the basis of our collective findings, we propose novel mechanisms for CsGSTosmediated survival and the differentiation of cholangiocytes in response to oxidative stress
Summary
Licensee MDPI, Basel, Switzerland.Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).Clonorchiasis, caused by the small liver fluke Clonorchis sinensis, represents one of the major fish-borne zoonotic helminthiases. Humans are infected by eating improperly cooked freshwater fish infected with the metacercariae. The disease is prevalent in severalAsian countries, where local ethnic dishes made of raw/undercooked freshwater fish are popular and widely consumed. About 15 million people are infected and another
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