Perez-Mancera, Pedro A. and Rust, Alistair G. and van der Weyden, Louise and Kristiansen, Glen and Li, Allen and Sarver, Aaron L. and Silverstein, Kevin A. T. and Gruetzmann, Robert and Aust, Daniela and Ruemmele, Petra and Knoesel, Thomas and Herd, Colin and Stemple, Derek L. and Kettleborough, Ross and Brosnan, Jacqueline A. and Li, Ang and Morgan, Richard and Knight, Spencer and Yu, Jun and Stegeman, Shane and Collier, Lara S. and ten Hoeve, Jelle J. and de Ridder, Jeroen and Klein, Alison P. and Goggins, Michael and Hruban, Ralph H. and Chang, David K. and Biankin, Andrew V. and Grimmond, Sean M. and Wessels, Lodewyk F. A. and Wood, Stephen A. and Iacobuzio-Donahue, Christine A. and Pilarsky, Christian and Largaespada, David A. and Adams, David J. and Tuveson, David A. (2012) The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. NATURE, 486 (7402). 266-+. ISSN 0028-0836, 1476-4687
Full text not available from this repository. (Request a copy)Abstract
Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations(1-4) in addition to numerous lower frequency genetic events of uncertain significance(5). Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis(6,7) in a mouse model of pancreatic ductal preneoplasia(8) to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia(9), we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SOMATIC MUTATIONS; INSERTION SITES; K-RAS; GENE; CANCER; MOUSE; MUTAGENESIS; CARCINOMA; EXPRESSION; STABILIZATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 May 2020 12:10 |
| Last Modified: | 11 May 2020 12:10 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18583 |
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