MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:30763770", "kind": "science-record", "revision": 7, "content_hash": "sha256:4845247969c1bef98a842acd0978f70759d51a29b49fd433aad9eb043d213b6d", "created_at": "2026-11-01T15:40:42Z", "updated_at": "2026-11-01T22:00:22Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma.", "doi": "10.1016/j.jcmgh.2019.01.008", "pmid": "30763770", "authors": ["Timothy A Dinh", "Mark L Jewell", "Matt Kanke", "Adam Francisco", "Ramja Sritharan", "Rigney E Turnham", "Seona Lee", "Edward R Kastenhuber", "Eliane Wauthier", "Cynthia D Guy", "Raymond S Yeung", "Scott W Lowe", "Lola M Reid", "John D Scott", "Anna M Diehl", "Praveen Sethupathy"], "journal": "Cellular and molecular gastroenterology and hepatology", "year": 2019, "abstract": "BACKGROUND & AIMS: Fibrolamellar carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. It is characterized by a heterozygous approximately 400-kb deletion on chromosome 19 that results in a unique fusion between DnaJ heat shock protein family member B1 (DNAJB1) and the alpha catalytic subunit of protein kinase A (PRKACA). The role of microRNAs (miRNAs) in FLC remains unclear. We identified dysregulated miRNAs in FLC and investigated whether dysregulation of 1 key miRNA contributes to FLC pathogenesis.\nMETHODS: We analyzed small RNA sequencing (smRNA-seq) data from The Cancer Genome Atlas to identify dysregulated miRNAs in primary FLC tumors and validated the findings in 3 independent FLC cohorts. smRNA-seq also was performed on a FLC patient-derived xenograft model as well as purified cell populations of the liver to determine whether key miRNA changes were tumor cell-intrinsic. We then used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (Cas9) technology and transposon-mediated gene transfer in mice to determine if the presence of DNAJB1-PRKACA is sufficient to suppress miR-375 expression. Finally, we established a new FLC cell line and performed colony formation and scratch wound assays to determine the functional consequences of miR-375 overexpression.\nRESULTS: We identified miR-375 as the most dysregulated miRNA in primary FLC tumors (27-fold down-regulation; P = .009). miR-375 expression also was decreased significantly in a FLC patient-derived xenograft model compared to 4 different cell populations of the liver. Introduction of DNAJB1-PRKACA by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 engineering and transposon-mediated somatic gene transfer in mice was sufficient to induce significant loss of miR-375 expression (P < .05). Overexpression of miR-375 in FLC cells inhibited Hippo signaling pathway proteins, including yes-associated protein 1 and connective tissue growth factor, and suppressed cell proliferation and migration (P < .05).\nCONCLUSIONS: We identified miR-375 as the most down-regulated miRNA in FLC tumors and showed that overexpression of miR-375 mitigated tumor cell growth and invasive potential. These findings open a potentially new molecular therapeutic approach. Further studies are necessary to determine how DNAJB1-PRKACA suppresses miR-375 expression and whether miR-375 has additional important targets in this tumor. 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METHODS: We analyzed small RNA sequencing (smRNA-seq) data from The Cancer Genome Atla", "left). Principal component analysis of small RNA-seq data from a FLC PDX model and 4 maturational", "omiRs (miR-182-5p and miR-10b-5p) from small RNA-seq in 4 maturational lineage stages of the live"], "order_basis": "paper_text_order:603", "id": "assay:1"}, {"role": "data_generation", "definition_id": "clinical_cohort", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["horts. smRNA-seq also was performed on a FLC patient-derived xenograft model as well as purified cell pop", "on also was decreased significantly in a FLC patient-derived xenograft model compared to 4 different cell", "MiR-375 Is Dramatically Suppressed in an FLC Patient-Derived Xenograft Model Compared With Every Major Li", "miR-375 is dramatically suppressed in an FLC patient-derived xenograft model relative to every lineage st"], "order_basis": "paper_text_order:813", "id": "assay:2"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ularly interspaced short palindromic repeats/CRISPR-associated protein 9 (Cas9) technology and t", "ularly interspaced short palindromic repeats/CRISPR-associated protein 9 engineering and transpo"], "order_basis": "paper_text_order:1032", "id": "assay:3"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["nology and transposon-mediated gene transfer in mice to determine if the presence of DNAJB1-PRKAC", "nd transposon-mediated somatic gene transfer in mice was sufficient to induce significant loss of", "nd 31281 (University of Washington). Animals Mice were treated as previously described.8 Briefly, f", "8 Briefly, female 6- to 10-week-old C57BL6/N mice were subjected to hydrodynamic tail-vein injectio"], "order_basis": "paper_text_order:1116", "id": "assay:4"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["Student t test"], "order_basis": "consumes_earlier_output", "id": "assay:5"}]}