A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells.
The human liver fluke, Opisthorchis viverrini, infects millions of people throughout south-east Asia and is a major cause of cholangiocarcinoma, or cancer of the bile ducts. The mechanisms by which chronic infection with O. viverrini results in cholangiocarcinogenesis are multi-factorial, but one such mechanism is the secretion of parasite proteins with mitogenic properties into the bile ducts, driving cell proliferation and creating a tumorigenic environment. Using a proteomic approach, we identified a homologue of human granulin, a potent growth factor involved in cell proliferation and wound healing, in the excretory/secretory (ES) products of the parasite. O. viverrini granulin, termed Ov-GRN-1, was expressed in most parasite tissues, particularly the gut and tegument. Furthermore, Ov-GRN-1 was detected in situ on the surface of biliary epithelial cells of hamsters experimentally infected with O. viverrini. Recombinant Ov-GRN-1 was expressed in E. coli and refolded from inclusion bodies. Refolded protein stimulated proliferation of murine fibroblasts at nanomolar concentrations, and proliferation was inhibited by the MAPK kinase inhibitor, U0126. Antibodies raised to recombinant Ov-GRN-1 inhibited the ability of O. viverrini ES products to induce proliferation of murine fibroblasts and a human cholangiocarcinoma cell line in vitro, indicating that Ov-GRN-1 is the major growth factor present in O. viverrini ES products. This is the first report of a secreted growth factor from a parasitic worm that induces proliferation of host cells, and supports a role for this fluke protein in establishment of a tumorigenic environment that may ultimately manifest as cholangiocarcinoma.
Smout
Michael J
MJ
Division of Infectious Diseases, Queensland Institute of Medical Research, Queensland, Australia.
Laha
Thewarach
T
Mulvenna
Jason
J
Sripa
Banchob
B
Suttiprapa
Sutas
S
Jones
Alun
A
Brindley
Paul J
PJ
Loukas
Alex
A
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000469:parasitology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000469:parasitology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D018281:Cholangiocarcinoma / Q000469:parasitology* / Q000473:pathology; D006224:Cricetinae; D000939:Epitopes / Q000276:immunology; D005210:Fasciola hepatica / Q000472:pathogenicity* / Q000502:physiology*; D000077155:Granulins; D006133:Growth Substances / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D010802:Phylogeny; D017510:Protein Folding
D000906:Antibodies; D000939:Epitopes; D000077155:Granulins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins