{"doi":"10.1371/journal.ppat.1010839","title":"Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini","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.","journal":"PLoS Pathogens","year":2022,"id":249529,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":890231,"name":"Sirikachorn Tangkawattana","orcid":"0000-0002-5662-8636","position":1,"is_corresponding":false},{"id":366939,"name":"Michael J. Smout","orcid":"0000-0001-6937-0112","position":2,"is_corresponding":false},{"id":417793,"name":"Wannaporn Ittiprasert","orcid":"0000-0001-9411-8883","position":3,"is_corresponding":false},{"id":445934,"name":"Victoria H. Mann","orcid":"0000-0002-2218-597X","position":4,"is_corresponding":false},{"id":890232,"name":"Raksawan Deenonpoe","orcid":"0000-0002-8387-6061","position":5,"is_corresponding":false},{"id":505146,"name":"Patpicha Arunsan","orcid":"0000-0001-5811-712X","position":6,"is_corresponding":false},{"id":242752,"name":"Alex Loukas","orcid":"0000-0002-0896-8441","position":7,"is_corresponding":false},{"id":366938,"name":"Paul J. Brindley","orcid":"0000-0003-1765-0002","position":8,"is_corresponding":false},{"id":366940,"name":"Thewarach Laha","orcid":"0000-0003-1334-9976","position":9,"is_corresponding":false},{"id":366937,"name":"Sujittra Chaiyadet","orcid":"0000-0002-8536-8589","position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-19T00:24:23.754337Z","pmid":"36137145","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}