A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma.
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.
Keng
Vincent W
VW
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Villanueva
Augusto
A
Chiang
Derek Y
DY
Dupuy
Adam J
AJ
Ryan
Barbara J
BJ
Matise
Ilze
I
Silverstein
Kevin A T
KA
Sarver
Aaron
A
Starr
Timothy K
TK
Akagi
Keiko
K
Tessarollo
Lino
L
Collier
Lara S
LS
Powers
Scott
S
Lowe
Scott W
SW
Jenkins
Nancy A
NA
Copeland
Neal G
NG
Llovet
Josep M
JM
Largaespada
David A
DA
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D004251:DNA Transposable Elements / Q000235:genetics*; D005786:Gene Expression Regulation; D018773:Genes, erbB-1 / Q000235:genetics* / Q000502:physiology; D005821:Genetic Techniques; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000379:methods*; D019895:Transposases / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000502:physiology
D004251:DNA Transposable Elements; D044763:Ubiquitin-Conjugating Enzymes; C045073:Cre recombinase; D019426:Integrases; D019895:Transposases