| First Author | Moser R | Year | 2012 |
| Journal | Mol Cancer Res | Volume | 10 |
| Issue | 4 | Pages | 535-45 |
| PubMed ID | 22301954 | Mgi Jnum | J:205393 |
| Mgi Id | MGI:5544712 | Doi | 10.1158/1541-7786.MCR-11-0508 |
| Citation | Moser R, et al. (2012) MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency. Mol Cancer Res 10(4):535-45 |
| abstractText | MYC-induced DNA damage is exacerbated in WRN-deficient cells, leading to replication stress and accelerated cellular senescence. To determine whether WRN deficiency impairs MYC-driven tumor development, we used both xenograft and autochthonous tumor models. Conditional silencing of WRN expression in c-MYC overexpressing non-small cell lung cancer xenografts impaired both tumor establishment and tumor growth. This inhibitory effect of WRN knockdown was accompanied by increased DNA damage, decreased proliferation, and tumor necrosis. In the Emu-Myc mouse model of B-cell lymphoma, a germline mutation in the helicase domain of Wrn (Wrn(Deltahel/Deltahel)) resulted in a significant delay in emergence of lethal lymphomas, extending tumor-free survival by more than 30%. Analysis of preneoplastic B cells from Emu-Myc Wrn mutant mice revealed increased DNA damage, elevation of senescence markers, and decreased proliferation in comparison with cells from age-matched Emu-Myc mice. Immunohistochemical and global gene expression analysis of overt Emu-Myc Wrn(Deltahel/Deltahel) lymphomas showed a marked increase in expression of the CDK inhibitor, p16(Ink4a), as well as elevation of TAp63, a known mediator of senescence. Collectively, these studies show that in the context of Myc-associated tumorigenesis, loss of Wrn amplifies the DNA damage response, both in preneoplastic and neoplastic tissue, engaging activation of tumor suppressor pathways. This leads to inhibition of tumor growth and prolonged tumor-free survival. Targeting WRN or its enzymatic function could prove to be an effective strategy in the treatment of MYC-associated cancers. |
