Search

Multistep processes likely underlie cholangiocarcinogenesis induced by chronic infection with the fish-borne liver fluke, Opisthorchis viverrini . One process appears to be cellular proliferation of the host bile duct epithelia driven by excretory–secretory (ES) products of this pathogen. Specifically, the secreted growth factor Ov -GRN-1, a liver fluke granulin, is a prominent component of ES and a known driver of hyper-proliferation of cultured human and mouse cells in vitro . We show potent hyper-proliferation of human cholangiocytes induced by low nanomolar levels of recombinant Ov -GRN-1 and similar growth produced by low microgram concentrations of ES products and soluble lysates of the adult worm. To further explore the influence of Ov -GRN-1 on the flukes and the host cells, expression of Ov-grn-1 was repressed using RNA interference. Expression of Ov-grn-1 was suppressed by 95% by day 3 and by ~100% by day 7. Co-culture of Ov-grn-1 suppressed flukes with human cholangiocyte (H-69) or human cholangiocarcinoma (KKU-M214) cell lines retarded cell hyper-proliferation by 25% and 92%, respectively. Intriguingly, flukes in which expression of Ov - grn-1 was repressed were less viable in culture, suggesting that Ov -GRN-1 is an essential growth factor for survival of the adult stage of O. viverrini , at least in vitro . To summarize, specific knock down of Ov-grn-1 reduced in vitro survival and capacity of ES products to drive host cell proliferation. These findings may help to contribute to a deeper understanding of liver fluke induced cholangiocarcinogenesis. [ABSTRACT FROM AUTHOR]