Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor.

Autor:	Dorr C; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Minneapolis Medical Research Foundation, Minneapolis, Minnesota., Janik C; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Weg M; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Been RA; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Comparative and Molecular Biosciences, University of Minnesota, St. Paul, Minnesota., Bader J; Massachusetts Institute of Technology, Cambridge, Massachusetts., Kang R; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Ng B; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Foran L; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Landman SR; Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota., O'Sullivan MG; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota. Comparative Pathology Shared Resource, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Steinbach M; Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota., Sarver AL; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Silverstein KA; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota., Largaespada DA; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Genetic, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota., Starr TK; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Genetic, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota. star0044@umn.edu.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2015 Aug; Vol. 13 (8), pp. 1238-47. Date of Electronic Publication: 2015 May 20.
DOI:	10.1158/1541-7786.MCR-14-0674-T
Abstrakt:	Unlabelled: Non-small cell lung cancers (NSCLC) harbor thousands of passenger events that hide genetic drivers. Even highly recurrent events in NSCLC, such as mutations in PTEN, EGFR, KRAS, and ALK, are detected, at most, in only 30% of patients. Thus, many unidentified low-penetrant events are causing a significant portion of lung cancers. To detect low-penetrance drivers of NSCLC, a forward genetic screen was performed in mice using the Sleeping Beauty (SB) DNA transposon as a random mutagen to generate lung tumors in a Pten-deficient background. SB mutations coupled with Pten deficiency were sufficient to produce lung tumors in 29% of mice. Pten deficiency alone, without SB mutations, resulted in lung tumors in 11% of mice, whereas the rate in control mice was approximately 3%. In addition, thyroid cancer and other carcinomas, as well as the presence of bronchiolar and alveolar epithelialization, in mice deficient for Pten were also identified. Analysis of common transposon insertion sites identified 76 candidate cancer driver genes. These genes are frequently dysregulated in human lung cancers and implicate several signaling pathways. Cullin3 (Cul3), a member of a ubiquitin ligase complex that plays a role in the oxidative stress response pathway, was identified in the screen and evidence demonstrates that Cul3 functions as a tumor suppressor. Implications: This study identifies many novel candidate genetic drivers of lung cancer and demonstrates that CUL3 acts as a tumor suppressor by regulating oxidative stress. (©2015 American Association for Cancer Research.)
Databáze:	MEDLINE
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