Targeted deletion of Wwox reveals a tumor suppressor function.
The WW domain-containing oxidoreductase (WWOX) spans the second most common fragile site of the human genome, FRA16D, located at 16q23, and its expression is altered in several types of human cancer. We have previously shown that restoration of WWOX expression in cancer cells suppresses tumorigenicity. To investigate WWOX tumor suppressor function in vivo, we generated mice carrying a targeted deletion of the Wwox gene and monitored incidence of tumor formation. Osteosarcomas in juvenile Wwox(-/-) and lung papillary carcinoma in adult Wwox(+/-) mice occurred spontaneously. In addition, Wwox(+/-) mice develop significantly more ethyl nitrosourea-induced lung tumors and lymphomas in comparison to wild-type littermate mice. Intriguingly, these tumors still express Wwox protein, suggesting haploinsuffiency of WWOX itself is cancer predisposing. These results indicate that WWOX is a bona fide tumor suppressor.
Aqeilan
Rami I
RI
Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, 410 West 12th Avenue, Columbus, OH 43210, USA. rami.aqeilan@osumc.edu
Trapasso
Francesco
F
Hussain
Sadiq
S
Costinean
Stefan
S
Marshall
Dean
D
Pekarsky
Yuri
Y
Hagan
John P
JP
Zanesi
Nicola
N
Kaou
Mohamed
M
Stein
Gary S
GS
Lian
Jane B
JB
Croce
Carlo M
CM
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016678:Genome; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012516:Osteosarcoma / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics*; D010641:Phenotype; D000074584:WW Domain-Containing Oxidoreductase
D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C428130:Wwox protein, mouse