Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini

Chaiyadet, Sujittra, Tangkawattana, Sirikachorn, Smout, Michael J., Ittiprasert, Wannaporn, Mann, Victoria H., Deenonpoe, Raksawan, Arunsan, Patpicha, Loukas, Alex, Brindley, Paul J., and Laha, Thewarach (2022) Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini. PLoS Pathogens, 18 (9). e1010839.

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Abstract

Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor for cholangiocarcinoma (CCA) in the Mekong Basin countries of Thailand, Lao PDR, Vietnam, Myanmar and Cambodia. Using a novel model of CCA, involving infection with gene-edited liver flukes in the hamster during concurrent exposure to dietary nitrosamine, we explored the role of the fluke granulin-like growth factor Ov-GRN-1 in malignancy. We derived RNA-guided gene knockout flukes (ΔOv-grn-1) using CRISPR/Cas9/gRNA materials delivered by electroporation. Genome sequencing confirmed programmed Cas9-catalyzed mutations of the targeted genes, which was accompanied by rapid depletion of transcripts and the proteins they encode. Gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes. However, less hepatobiliary tract disease manifested during chronic infection with ΔOv-grn-1 worms in comparison to hamsters infected with control gene-edited and mock-edited parasites. Specifically, immuno- and colorimetric-histochemical analysis of livers revealed markedly less periductal fibrosis surrounding the flukes and less fibrosis globally within the hepatobiliary tract during infection with ΔOv-grn-1 genotype worms, minimal biliary epithelial cell proliferation, and significantly fewer mutations of TP53 in biliary epithelial cells. Moreover, fewer hamsters developed high-grade CCA compared to controls. The clinically relevant, pathophysiological phenotype of the hepatobiliary tract confirmed a role for this secreted growth factor in malignancy and morbidity during opisthorchiasis.

Item ID: 76420
Item Type: Article (Research - C1)
ISSN: 1553-7374
Copyright Information: © 2022 Chaiyadet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Date Deposited: 27 Mar 2023 01:13
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3207 Medical microbiology > 320704 Medical parasitology @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321199 Oncology and carcinogenesis not elsewhere classified @ 50%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200104 Prevention of human diseases and conditions @ 100%
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