CRISPR/Cas9-based Pten knock-out and Sleeping Beauty Transposon-mediated Nras knock-in induces hepatocellular carcinoma and hepatic lipid accumulation in mice

Both Pten and Nras are downstream mediators of receptor tyrosine kinase activation that plays important roles in controlling cell survival and proliferation. Here, we investigated whether and how Pten loss cross-talks with Nras activation in driving liver cancer development in mice. Somatic disrupti...

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Bibliographic Details
Published in:Cancer biology & therapy 2017-07, Vol.18 (7), p.505-512
Main Authors: Gao, Mingming, Liu, Dexi
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
CRISPR-Cas Systems
Energy Metabolism
Gene Expression
Gene Knock-In Techniques
Gene Knockout Techniques
Gene Order
Gene Transfer Techniques
Genetic Vectors - genetics
Genome editing
Glycogen - metabolism
GTP Phosphohydrolases - genetics
hepatocellular carcinoma
hydrodynamic gene transfer
Immunohistochemistry
lipid droplet
Lipid Metabolism
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Male
Membrane Proteins - genetics
Mice
Mice, Knockout
Mice, Transgenic
nonalcoholic steatohepatitis
PTEN Phosphohydrolase - deficiency
PTEN Phosphohydrolase - genetics
Research Paper
Signal Transduction
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Summary:Both Pten and Nras are downstream mediators of receptor tyrosine kinase activation that plays important roles in controlling cell survival and proliferation. Here, we investigated whether and how Pten loss cross-talks with Nras activation in driving liver cancer development in mice. Somatic disruption of hepatic Pten and overexpression of Nras were achieved in out-bred immunocompetent CD-1 mice through a hydrodynamic delivery of plasmids carrying Sleeping Beauty transposon-based integration of Nras and the CRISPR/Cas9-mediated Pten knockout system. Concurrent Pten knockout and Nras knock-in induced hepatocellular carcinoma, while individual gene manipulation failed. Tumor development was associated with liver fibrosis, hyperlipidemia, hepatic deposition of lipid droplets and glycogen, and hepatomegaly. At the molecular level, lipid droplet formation was primarily contributed by upregulated expression of genes responsible for lipogenesis and fatty acid sequestration, such as Srebpf1, Acc, Pparg and its downstream targets. Our findings demonstrated that Pten disruption was synergized by Nras overexpression in driving hepatocyte malignant transformation, which correlated with extensive formation of lipid droplets.
ISSN:1538-4047
1555-8576
DOI:10.1080/15384047.2017.1323597