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A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells.
- Source :
-
PLoS pathogens [PLoS Pathog] 2009 Oct; Vol. 5 (10), pp. e1000611. Date of Electronic Publication: 2009 Oct 09. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Animals
Antibodies pharmacology
Bile Duct Neoplasms pathology
Bile Ducts, Intrahepatic parasitology
Cell Division drug effects
Cell Division physiology
Cholangiocarcinoma pathology
Cricetinae
Epitopes immunology
Granulins
Growth Substances physiology
Humans
Intercellular Signaling Peptides and Proteins genetics
Intercellular Signaling Peptides and Proteins immunology
Intercellular Signaling Peptides and Proteins physiology
Mice
Neoplasm Invasiveness pathology
Phylogeny
Protein Folding
Bile Duct Neoplasms parasitology
Cholangiocarcinoma parasitology
Fasciola hepatica pathogenicity
Fasciola hepatica physiology
Growth Substances metabolism
Intercellular Signaling Peptides and Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 5
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 19816559
- Full Text :
- https://doi.org/10.1371/journal.ppat.1000611