WWOX

Common fragile site gene WWOX encodes a candidate tumor suppressor WW domain-containing oxidoreductase.

Alteration of this gene, along with dramatic downregulation of WWOX protein, is shown in the majority of invasive cancer cells.

Ectopic WWOX exhibits proapoptotic and tumor inhibitory functions in vitro and in vivo, probably interacting with growth regulatory proteins p53, p73 and others.

Hyaluronidases regulate WWOX expression, increase cancer invasiveness and seem to be involved in the development of hormone-independent growth of invasive cancer cells.

Estrogen and androgen stimulate phosphorylation and nuclear translocation of WWOX, although binding of WWOX to these sex hormones is unknown.

WWOX is a putative tumor suppressor gene encoded within common chromosomal fragile site region FRA16D, in chromosome band 16q23.

Pathology

WWOX expression is often reduced or lost in various tumor types. WWOX tumor suppressor activity was suggested by re-expressing WWOX in breast, ovarian, and lung tumor cell lines leading to tumor growth inhibition in vivo.

Mouse models

 Mouse strain containing a Wwox gene mutated by a gene-trap vector. -* Wwox hypomorphs had an increased incidence of B-cell lymphomas supports a role of Wwox as a tumor suppressor.

Pathology

 WWOX gene inactivation in esophageal squamous cell carcinomas (MIM.133239)

• loss of heterozygosity (LOH) at the WWOX locus (39%)
• tumor-specific mutation

Referencs

 Ludes-Meyers JH, Kil H, Nunez MI, Conti CJ, Parker-Thornburg J, Bedford MT, Marcelo Aldaz C. WWOX hypomorphic mice display a higher incidence of B-cell lymphomas and develop testicular atrophy. Genes Chromosomes Cancer. 2007 Sep 6; PMID: 17823927

 Kuroki, T.; Trapasso, F.; Shiraishi, T.; Alder, H.; Mimori, K.; Mori, M.; Croce, C. M. : Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma. Cancer Res. 62: 2258-2260, 2002. PubMed ID : 11956080

 Paige, A. J. W.; Taylor, K. J.; Taylor, C.; Hillier, S. G.; Farrington, S.; Scott, D.; Porteous, D. J.; Smyth, J. F.; Gabra, H.; Watson, J. E. V. : WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc. Nat. Acad. Sci. 98: 11417-11422, 2001. PubMed ID : 11572989

 Ried, K.; Finnis, M.; Hobson, L.; Mangelsdorf, M.; Dayan, S.; Nancarrow, J. K.; Woollatt, E.; Kremmidiotis, G.; Gardner, A.; Venter, D.; Baker, E.; Richards, R. I. : Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells. Hum. Molec. Genet. 9: 1651-1663, 2000. PubMed ID : 10861292