The research deals with cholangiocarcinoma (CCA), bile duct cancer, caused by infection with the liver fluke, Opisthorchis viverrini. CCA is a primary cancer originating in the epithelium (cholangiocytes) ofthe bile ducts. It has long latency, is invasive, metastasizes and has a dismal prognosis. The mechanisms by which chronic infection with the flukes results in CCA are likely multi-factorial, but one mechanism is the secretion of parasite proteins with mitogenic and anti-apoptotic properties, both features of a pre-cancerous cellular environment. We have characterised the excretory/secretory (ES) products of O. viverrini and identified two candidate ES proteins that are central to these processes - we showed that a homologue of the human secreted growth factor, granulin, binds to cholangiocytes and stimulates proliferation of fibroblasts and CCA cell lines. We also showed that secreted thioredoxin peroxidase blocks apoptosis of damaged cholangiocytes. Progression of chronic opisthorchiasis to CCA follows a multi-factorial route(s). We hypothesize that key processes along the route include (1) secretion of parasite proteins which induce pathology in the biliary tract and establish an environment conducive to cancer development by promoting cell proliferation and DNA damage, accelerating wound healing and blocking apoptosis;and (2) repeated administration of the anthelmintic drug praziquantel, for treatment of O. viverrini (Ov) infection, causes increased inflammation in the bile ducts and thereby precipitates tumorigenesis. The research will investigate these phenomena by assessing the ability of Ov-ES to (1) facilitate wound repair in mammalian cells;(2) promote cell invasion and migration;(3) interfere with apoptosis. To further address the carcinogenic roles of these proteins, we will vaccinate hamsters with Ov-ES and its defined components to determine whether this intervention can protect against liver fluke infection and CCA, and assessment of impact of repeated PZQ therapy in accelerating tumorigenesis.

Public Health Relevance

Despite treatment and health education campaigns, the prevalence of O. viverrini infection remains high in Northeast Thailand;more problematically, infection with O. viverrini often leads to a deadly form of liver cancer. The work proposed here investigates - at the molecular level - how liver fluke infection causes this liver cancer, and could offer new strategies to control this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center (P50)
Project #
4P50AI098639-02
Application #
8495207
Study Section
Special Emphasis Panel (ZAI1-AWA-M)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$112,419
Indirect Cost
$7,136
Name
Khon Kaen University
Department
Type
DUNS #
659454446
City
Khon Kaen
State
Country
Thailand
Zip Code
40002
Thanasuwan, Sirikanda; Piratae, Supawadee; Brindley, Paul J et al. (2014) Suppression of aquaporin, a mediator of water channel control in the carcinogenic liver fluke, Opisthorchis viverrini. Parasit Vectors 7:224
Thi Phung, Luyen; Loukas, Alex; Brindley, Paul J et al. (2014) Retrotransposon OV-RTE-1 from the carcinogenic liver fluke Opisthorchis viverrini: potential target for DNA-based diagnosis. Infect Genet Evol 21:443-51
Plieskatt, Jordan L; Rinaldi, Gabriel; Feng, Yanjun et al. (2014) Distinct miRNA signatures associate with subtypes of cholangiocarcinoma from infection with the tumourigenic liver fluke Opisthorchis viverrini. J Hepatol 61:850-8
Plieskatt, Jordan L; Deenonpoe, Raksawan; Mulvenna, Jason P et al. (2013) Infection with the carcinogenic liver fluke Opisthorchis viverrini modifies intestinal and biliary microbiome. FASEB J 27:4572-84
Saichua, Prasert; Sithithaworn, Paiboon; Jariwala, Amar R et al. (2013) Microproteinuria during Opisthorchis viverrini infection: a biomarker for advanced renal and hepatobiliary pathologies from chronic opisthorchiasis. PLoS Negl Trop Dis 7:e2228