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MRNA expression profiling of hepatocellular carcinoma induced by AAV in vivo gene targeting at the Rian locus

ABSTRACT: The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting ~1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300 kb chromosomal domain containing multiple mRNAs, snoRNAs and microRNAs was activated surrounding the integration site. An identical domain was activated at the syntenic locus in a specific molecular subclass of spontaneous human HCCs with a similar histological phenotype, which was associated with partial loss of DNA methylation. These findings demonstrate the accuracy of in vivo gene targeting in modeling human cancer, and suggest future applications in studying various tumors in diverse animal species. In addition, similar insertion events produced by randomly integrating vectors could be a concern for liver-directed human gene therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE35403 | GEO | 2012/07/03

SECONDARY ACCESSION(S): PRJNA156061

REPOSITORIES: GEO

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miRNA expression profiling of hepatocellular carcinoma induced by AAV in vivo gene targeting at the Rian locus

Project description:The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting ~1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300 kb chromosomal domain containing multiple mRNAs, snoRNAs and microRNAs was activated surrounding the integration site. An identical domain was activated at the syntenic locus in a specific molecular subclass of spontaneous human HCCs with a similar histological phenotype, which was associated with partial loss of DNA methylation. These findings demonstrate the accuracy of in vivo gene targeting in modeling human cancer, and suggest future applications in studying various tumors in diverse animal species. In addition, similar insertion events produced by randomly integrating vectors could be a concern for liver-directed human gene therapy. Three individual liver tumor samples and their adjacent normal-looking liver tissue were used for miRNA array analysis

2012-07-02 | E-GEOD-35402 | biostudies-arrayexpress

mRNA expression profiling of hepatocellular carcinoma induced by AAV in vivo gene targeting at the Rian locus

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2012-07-02 | E-GEOD-35403 | biostudies-arrayexpress

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miRNA and mRNA expression profiling of hepatocellular carcinoma induced by AAV in vivo gene targeting at the Rian locus

Project description:This SuperSeries is composed of the following subset Series: GSE35402: miRNA expression profiling of hepatocellular carcinoma induced by AAV in vivo gene targeting at the Rian locus GSE35403: mRNA expression profiling of hepatocellular carcinoma induced by AAV in vivo gene targeting at the Rian locus Refer to individual Series

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Genotoxicity after adeno-associated virus (AAV) gene therapy is dependent upon dose, treatment age and enhancer-promoter selection (microRNA)

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