Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD(+)) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD(+) pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD(+) can be prophylactic or therapeutic in HCC.
Sample name | Organism | Experiment title | Sample type | Library instrument | Attributes | |||||||||||||||||||||||||||||||||||||||||||||||||
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duration of huri expression | ectopic expression | source name | strain/background | tissue | ||||||||||||||||||||||||||||||||||||||||||||||||||
8 weeks Unconventional prefoldin RPB5 interactor overexpression, replicate 3 | Mus musculus | GSM1182954: 8 weeks URI overexpression, replicate 3; Mus musculus; RNA-Seq | RNA-Seq | Illumina Genome Analyzer IIx | 8 weeks | hURI | Liver, hURI expression, 8 weeks | C57BL/6 | liver (bottom half of right lobe) | |||||||||||||||||||||||||||||||||||||||||||||
8 weeks Unconventional prefoldin RPB5 interactor overexpression, replicate 2 | Mus musculus | GSM1182953: 8 weeks URI overexpression, replicate 2; Mus musculus; RNA-Seq | RNA-Seq | Illumina Genome Analyzer IIx | 8 weeks | hURI | Liver, hURI expression, 8 weeks | C57BL/6 | liver (bottom half of right lobe) | |||||||||||||||||||||||||||||||||||||||||||||
8 weeks Unconventional prefoldin RPB5 interactor overexpression, replicate 1 | Mus musculus | GSM1182952: 8 weeks URI overexpression, replicate 1; Mus musculus; RNA-Seq | RNA-Seq | Illumina Genome Analyzer IIx | 8 weeks | hURI | Liver, hURI expression, 8 weeks | C57BL/6 | liver (bottom half of right lobe) | |||||||||||||||||||||||||||||||||||||||||||||
8 weeks control, replicate 4 | Mus musculus | GSM1182951: 8 weeks control, replicate 4; Mus musculus; RNA-Seq | RNA-Seq | Illumina Genome Analyzer IIx | 8 weeks | none | Liver, control, 8 weeks | C57BL/6 | liver (bottom half of right lobe) | |||||||||||||||||||||||||||||||||||||||||||||
8 weeks control, replicate 3 | Mus musculus | GSM1182950: 8 weeks control, replicate 3; Mus musculus; RNA-Seq | RNA-Seq | Illumina Genome Analyzer IIx | 8 weeks | none | Liver, control, 8 weeks | C57BL/6 | liver (bottom half of right lobe) |