A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma

Keng, V. W., Villanueva, A., Chiang, D. Y., Dupuy, A. J., Ryan, B. J., Matise, I., Silverstein, K. A. T., Sarver, A., Starr, T. K., Akagi, K., Tessarollo, L., Collier, L. S., Powers, S., Lowe, S. W., Jenkins, N. A., Copeland, N. G., Llovet, J. M., Largaespada, D. A. (March 2009) A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma. Nature Biotechnology, 27 (3). pp. 264-274. ISSN 1087-0156

URL: http://www.ncbi.nlm.nih.gov/pubmed/19234449
DOI: 10.1038/nbt.1526

Abstract

We describe a system that permits conditional mobilization of a Sleeping Beauty (SB) transposase allele by Cre recombinase to induce cancer specifically in a tissue of interest. To demonstrate its potential for developing tissue-specific models of cancer in mice, we limit SB transposition to the liver by placing Cre expression under the control of an albumin enhancer/promoter sequence and screen for hepatocellular carcinoma (HCC)-associated genes. From 8,060 nonredundant insertions cloned from 68 tumor nodules and comparative analysis with data from human HCC samples, we identify 19 loci strongly implicated in causing HCC. These encode genes, such as EGFR and MET, previously associated with HCC and others, such as UBE2H, that are potential new targets for treating this neoplasm. Our system, which could be modified to drive transposon-based insertional mutagenesis wherever tissue-specific Cre expression is possible, promises to enhance understanding of cancer genomes and identify new targets for therapeutic development.

Item Type: Paper
Uncontrolled Keywords: GROWTH-FACTOR-RECEPTOR NF-KAPPA-B SLEEPING-BEAUTY IN-VITRO LIVER-CANCER EXPRESSION KINASE TUMOR ACTIVATION PATHWAY
Subjects: bioinformatics
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > cancer > cancer types > liver cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transposons
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Lowe lab
CSHL labs > Powers lab
Depositing User: Matt Covey
Date: March 2009
Date Deposited: 21 Feb 2013 21:12
Last Modified: 21 Feb 2013 21:12
PMCID: PMC2712727
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27348

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