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http://purl.uniprot.org/citations/28923495 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/28923495 | http://www.w3.org/2000/01/rdf-schema#comment | "Background & aimsFibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects children and young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1-PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1-Prkaca fusion and monitored the mice for liver tumor development.MethodsWe delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1-Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8-week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1-Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing.ResultsLivers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms. The tumors contained the Dnajb1-Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1-Prkaca fusion revealed a lack of mutations in genes commonly associated with liver cancers, as observed in human FL-HCC.ConclusionsUsing CRISPR/Cas9 technology, we found generation of the Dnajb1-Prkaca fusion gene in wild-type mice to be sufficient to initiate formation of tumors that have many features of human FL-HCC. Strategies to block DNAJB1-PRKACA might be developed as therapeutics for this form of liver cancer."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.org/dc/terms/identifier | "doi:10.1053/j.gastro.2017.09.008"xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Johansen J.V."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Serra D."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Riaz A."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Hansen S.H."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Santoni-Rugiu E."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Engelholm L.H."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Dagnaes-Hansen F."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Frodin M."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/author | "Niola F."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/date | "2017"xsd:gYear |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/name | "Gastroenterology"xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/pages | "1662-1673.e10"xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/title | "CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma."xsd:string |
http://purl.uniprot.org/citations/28923495 | http://purl.uniprot.org/core/volume | "153"xsd:string |
http://purl.uniprot.org/citations/28923495 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/28923495 |
http://purl.uniprot.org/citations/28923495 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/28923495 |
http://purl.uniprot.org/uniprot/#_J9JDU9-mappedCitation-28923495 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/28923495 |
http://purl.uniprot.org/uniprot/#_Q3TU79-mappedCitation-28923495 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/28923495 |
http://purl.uniprot.org/uniprot/#_P05132-mappedCitation-28923495 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/28923495 |
http://purl.uniprot.org/uniprot/#_Q3TYL7-mappedCitation-28923495 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/28923495 |
http://purl.uniprot.org/uniprot/#_Q3TIT6-mappedCitation-28923495 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/28923495 |
http://purl.uniprot.org/uniprot/#_Q9QYJ3-mappedCitation-28923495 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/28923495 |