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

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Mei Xu

PROVIDER: E-GEOD-35404 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Induction of hepatocellular carcinoma by in vivo gene targeting.

Wang Pei-Rong PR Xu Mei M Toffanin Sara S Li Yi Y Llovet Josep M JM Russell David W DW

Proceedings of the National Academy of Sciences of the United States of America 20120625 28

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 ...[more]

PMID: 22733778

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mRNA 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 tissue and their adjacent normal liver tissue were used for mRNA array analysis

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

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

Ankrd2 silencing

Project description:CHQ5B primary human myoblasts obtained from Dr V. Mouly (Paris, France) have been described previously (Faulkner et al., 1999). Ankrd2 is upregulated on differentiation of myoblasts. The change in gene expression was studied in cells silenced for Ankrd2 (infected with AAV-shAnkrd2), control cells (infected with AAV-shLuc) and control cells uninfected.

2011-12-31 | E-MEXP-2949 | biostudies-arrayexpress

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Project description:We used AAV as a vector to deliver hGRÎ² to the liver of GR Liver Knockout mice. We collected liver samples for microarray analysis to investigate any phenotype as well as the underlying specific signaling pathway. In particular, we would like to determine if and how hGRÎ² overexpression in liver affects mGRÎ±âs gene transcription profile in GR Liver Knockout mice. GR Liver Knockout mice were treated with PBS, AAV-GFP and AAV-hGRB, respectively. Each treatment group has four replicates.

2015-12-11 | E-GEOD-75683 | biostudies-arrayexpress

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

Project description:AAV gene therapy has recently been approved for clinical use and shown to be efficacious and safe in a growing number of clinical trials. However, the safety of AAV as a gene therapy has been challenged by a few studies that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. The association between AAV and HCC has been difficult to reconcile and is the subject of intense debate because numerous AAV studies have not reported toxicity. Here, we report a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the Rian locus and the over-expression of a proximal gene, Rtl1, were associated with HCC. In addition, we identify a number of genes with differential expression that maybe useful in the study, diagnosis and treatment of HCC. We demonstrate that AAV vector dose, enhancer-promoter selection, and the timing of gene delivery are the defining factors in AAV-mediated insertional mutagenesis. Our results help explain the AAV-mediated genotoxicity previously observed and have important implications for the design of both safer AAV vectors and gene therapy studies. To investigate the possibility that insertional mutagenesis by AAV contributed to the development of HCC, we collected normal and tumor tissues from adult mouse livers that received AAV injection at a neonatal stage.

2015-01-01 | E-GEOD-57597 | biostudies-arrayexpress

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

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Project description:To initially determine changes on the transcriptome level that might account for the phenotypic observations in an unbiased fashion, we performed large-scale mRNA expression profiling 8 weeks after treatment with an AAV harboring a control or GAbpa-specific miRNA under the LP1 promoter. Mice were subjected to 16 h fasting or a 16 h fasting + 6 h refeeding cycle before termination of the experiment. All 8 AAV-injected experimental groups as NC and GAbpÎ± knockdown samples for the different conditions (wt or db/db; fasting or refeeding) were included.

2017-05-31 | E-MTAB-5775 | biostudies-arrayexpress

Transcription profiling of rat nucleus accumbens shell shows CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits

Project description:We are comparing the gene expression patterns from rats in which they are either double housed or socially isolated. Within these groups we performed the following manipulations: AAV-GFP to the NAc shell AAV-CREB to the NAc shell chronic imipramine treatment water control

2009-01-01 | E-MEXP-1944 | biostudies-arrayexpress

Transcription profiling of livers from Low Density Lipoprotein Receptor null mice expressing human LXR alpha to explore the molecular basis of metabolic effects of increased hepatic hLXR alpha.

Project description:Microarray analysis of liver RNA from male Low Density Lipoprotein Receptor null mice on C57B6 background expressing human LXR alpha or GFP (control) via adeno-associated virus (AAV2.8) gene transfer, under control of the liver specific human thyroxine binding globulin promoter. Samples are from 8 month old mice, with AAV treatment at age of 10 weeks, on Western diet for 12 weeks prior experiment. The synthetic LXR ligand T0901317 (5mg/kg) or vehicle was administered for 3 days by i.p. injection to designated mice.

2007-08-31 | E-GEOD-2644 | biostudies-arrayexpress

Functional characterization of hGRÎ² Isoform in mouse liver

Project description:We used AAV as a vector to deliver hGRÎ² to C57BL/6 mouse liver. We collected liver samples for microarray analysis to investigate any phenotype as well as the underlying specific signaling pathway. In particular, we would like to determine if and how hGRÎ² overexpression in liver affects mGRÎ±âs gene transcription profile in C57BL/6 mice. Three replicates for each group: untreated WT liver, AAV-GFP treated liver, and AAV-hGRB treated liver.

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