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PMID: 19234449 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature biotechnology ·Vol. 27 ·No. 3 ·2009-03-00 ·Pages 264-74

Keng VW, Villanueva A, Chiang DY, Dupuy AJ, Ryan BJ, Matise I, Silverstein KA, Sarver A, Starr TK, Akagi K, Tessarollo L, Collier LS, Powers S, Lowe SW, Jenkins NA, Copeland NG, Llovet JM, Largaespada DA

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.

MeSH Terms
Adenoma/genetics,pathology Animals Carcinoma, Hepatocellular/genetics,pathology DNA Transposable Elements/genetics Gene Expression Regulation Genes, erbB-1/genetics,physiology Genetic Techniques Humans Integrases/genetics,metabolism Liver/metabolism Liver Neoplasms, Experimental/genetics,metabolism,pathology Male Mice Mice, Transgenic Mutagenesis, Insertional/methods Transposases/genetics,metabolism Ubiquitin-Conjugating Enzymes/genetics,physiology
Chemicals
DNA Transposable Elements Ubiquitin-Conjugating Enzymes Cre recombinase Integrases Transposases
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Keng Vincent W
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Villanueva Augusto
Chiang Derek Y
Dupuy Adam J
Ryan Barbara J
Matise Ilze
Silverstein Kevin A T
Sarver Aaron
Starr Timothy K
Akagi Keiko
Tessarollo Lino
Collier Lara S
Powers Scott
Lowe Scott W
Jenkins Nancy A
Copeland Neal G
Llovet Josep M
Largaespada David A
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Article Info
Journal
Nature biotechnology
Abbr.
Nat Biotechnol
ISSN
1546-1696
DOI
10.1038/nbt.1526
Published
2009-03-00
Epub
2009-00-22
Pages
264-74
Language
English
Region
United States
NLM ID
9604648
PMCID
PMC2712727
Subset
IM
Grants
NIDDK NIH HHS · 1R01DK076986-01 · United States
NCI NIH HHS · U01 CA084221 · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · R01 CA113636 · United States
NCI NIH HHS · 1K01CA122183-01 · United States
NCI NIH HHS · K01 CA122183 · United States
NCI NIH HHS · U01 CA84221 · United States
NIDDK NIH HHS · R01 DK076986 · United States
NCI NIH HHS · R01 CA113636-01A1 · United States
Corrections
CommentIn
PMID: 19479787
External Links
PubMed source DOI: 10.1038/nbt.1526 PMC Full Text View journal details
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