Excretory/secretory products of the carcinogenic liver fluke are endocytosed by human cholangiocytes and drive cell proliferation and IL6 production

Chaiyadet, Sujittra, Smout, Michael, Johnson, Michael, Whitchurch, Cynthia, Turnbull, Lynne, Kaewkes, Sasithorn, Sotillo, Javier, Loukas, Alex, and Sripa, Banchob (2015) Excretory/secretory products of the carcinogenic liver fluke are endocytosed by human cholangiocytes and drive cell proliferation and IL6 production. International Journal for Parasitology, 45 (12). pp. 773-781.

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Liver fluke infection caused by Opisthorchis viverrini remains a major public health problem in many parts of Asia including Thailand, Lao PDR, Vietnam and Cambodia, where there is a strikingly high incidence of cholangiocarcinoma (CCA – hepatic cancer of the bile duct epithelium). Among other factors, uptake of O. viverrini excretory/secretory products (OvES) by biliary epithelial cells has been postulated to be responsible for chronic inflammation and proliferation of cholangiocytes, but the mechanisms by which cells internalise O. viverrini excretory/secretory products are still unknown. Herein we incubated normal human cholangiocytes (H69), human cholangiocarcinoma cells (KKU-100, KKU-M156) and human colon cancer (Caco-2) cells with O. viverrini excretory/secretory products and analysed the effects of different endocytic inhibitors to address the mechanism of cellular uptake of ES proteins. Opisthorchis viverrini excretory/secretory products was internalised preferentially by liver cell lines, and most efficiently/rapidly by H69 cells. There was no evidence for trafficking of ES proteins to cholangiocyte organelles, and most of the fluorescence was detected in the cytoplasm. Pretreatment with clathrin inhibitors significantly reduced the uptake of O. viverrini excretory/secretory products, particularly by H69 cells. Opisthorchis viverrini excretory/secretory products induced proliferation of liver cells (H69 and CCA lines) but not intestinal (Caco-2) cells, and proliferation was blocked using inhibitors of the classical endocytic pathways (clathrin and caveolae). Opisthorchis viverrini excretory/secretory products drove IL6 secretion by H69 cells but not Caco-2 cells, and cytokine secretion was significantly reduced by endocytosis inhibitors. This the first known study to address the endocytosis of helminth ES proteins by host epithelial cells and sheds light on the pathways by which this parasite causes one of the most devastating forms of cancer in south-eastern Asia.

Item ID: 40285
Item Type: Article (Research - C1)
ISSN: 1879-0135
Keywords: Opisthorchis viverrini; endocytosis; carcinogenesis; excretory/secretory products; IL6; cholangiocyte;
Funders: National Health Security of Thailand, Thailand Research Fund (TRF), National Institute of Allergy and Infectious Disease (NIAID), National Cancer Institute (NCI), National Institute of Health (NIH), USA, National Health and Medical Research Council of Australia (NHMRC), United States Army Medical Research and Material Command (USAMRMC)
Projects and Grants: TRF Senior Scholar RTA 5680006, NIAID award P50A1098639, NCI CA155297, NCI R01CA CA164719, USAMRMC W81XWH-12-C-0267, TRF Royal Golden Jubilee no. PHD/0205/2551
Date Deposited: 05 Nov 2015 03:41
FoR Codes: 06 BIOLOGICAL SCIENCES > 0603 Evolutionary Biology > 060307 Host-Parasite Interactions @ 70%
11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110803 Medical Parasitology @ 10%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060108 Protein Trafficking @ 20%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 50%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 50%
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