Abstract
BackgroundClonorchis sinensis is a group I bio-carcinogen responsible for cholangiocarcinoma (CHCA) in humans. However, the mechanism by which C. sinensis promotes carcinogenesis is unclear.MethodologyUsing the human cholangiocyte line H69, we investigated cell proliferation and gap junction protein expression after stimulation with the hepatotoxin N-nitrosodimethylamine (NDMA) and/or excretory-secretory products (ESP) of C. sinensis, which induce inflammation. NDMA and ESP treatment increased proliferation by 146% and the proportion of cells in the G2/M phase by 37%. Moreover, the expression of the cell proliferation-related proteins E2F1, Ki-67, and cancer related protein cytokeratin 19 and Cox-2 increased in response to combined treatment with NDMA and ESP. The gap-junction proteins connexin (Cx) 43 and Cx26 increased. In contrast, Cx32 expression decreased in cells treated with NDMA and ESP. Silencing of Cx43 reduced cell proliferation and significantly suppressed Cx26 and Cox-2 expression.ConclusionsThese results suggest that Cx43 is an important factor in CHCA induced by C. sinensis ESP and NDMA and further investigations targeting this pathway may allow prevention of this deadly disease.
Highlights
Clonorchis sinensis is a human liver fluke that induces cholangiocarcinoma (CHCA) in humans [1]
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. These results suggest that Cx43 is an important factor in CHCA induced by C. sinensis excretory-secretory products (ESP) and NDMA and further investigations targeting this pathway may allow prevention of this deadly disease
Connexin 43 is an important factor in human cholangiocarcinoma
Summary
Clonorchis sinensis is a human liver fluke that induces cholangiocarcinoma (CHCA) in humans [1]. The mechanism by which C. sinensis induces CHCA is not well understood, but chronic hepatobiliary damage, a precursor to CHCA, in clonorchiasis is a multi-factorial outcome of the mechanical and biochemical irritation of the biliary epithelium by flukes via their suckers, metabolites, and excretory-secretory products (ESP) [3]. N-nitrosodimethylamine (NDMA) is a potent hepatotoxin that can cause fibrosis and tumors in the liver of rats via the activation of CYP450 enzymes [10] and hamsters infected with C. sinensis are at a greater risk of developing NDMA-induced or inflammation-mediated CHCA than uninfected hamsters [11, 12]. Clonorchis sinensis is a group I bio-carcinogen responsible for cholangiocarcinoma (CHCA) in humans. The mechanism by which C. sinensis promotes carcinogenesis is unclear
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