A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer
| Autor: | Jef D. Boeke, Wei Rose Xie, Erin L. Reineke, Bert W. O'Malley, David A. Largaespada, Vincent W. Keng, Loris Mularoni, Michael Torbenson, Danhua Fan, Kathryn A. O'Donnell, Sarah J. Wheelan, Brian York, Kevin A. T. Silverstein, Christina T. Schrum, Daekwan Seo |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Alkylating Agents Liver tumor Carcinoma Hepatocellular DNA Mutational Analysis Transplantation Heterologous Genes myc Mutagenesis (molecular biology technique) Mice Nude Transposases Mice Transgenic Biology medicine.disease_cause Mice Nuclear Receptor Coactivator 2 medicine Animals Humans Diethylnitrosamine Genes Tumor Suppressor Genetics Gene knockdown Multidisciplinary Liver Neoplasms medicine.disease Transplantation Disease Models Animal HEK293 Cells PNAS Plus Cancer research Transposon mutagenesis Female Liver cancer Carcinogenesis Neoplasm Transplantation Genetic screen |
| Popis: | The Sleeping Beauty ( SB ) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC , one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/Src-2, Zfx, and Dtnb , as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy. |
| Databáze: | OpenAIRE |
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