Targeted deletion of Wwox reveals a tumor suppressor function

Rami I. Aqeilan*, Francesco Trapasso, Sadiq Hussain, Stefan Costinean, Dean Marshall, Yuri Pekarsky, John P. Hagan, Nicola Zanesi, Mohamed Kaou, Gary S. Stein, Jane B. Lian, Carlo M. Croce

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

184 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)3949-3954
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number10
DOIs
StatePublished - 6 Mar 2007
Externally publishedYes

Keywords

  • Common fragile site
  • FHIT
  • Knockout
  • Lung cancer
  • Osteosarcoma

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