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A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer.


ABSTRACT: 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.

SUBMITTER: O'Donnell KA 

PROVIDER: S-EPMC3361419 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer.

O'Donnell Kathryn A KA   Keng Vincent W VW   York Brian B   Reineke Erin L EL   Seo Daekwan D   Fan Danhua D   Silverstein Kevin A T KA   Schrum Christina T CT   Xie Wei Rose WR   Mularoni Loris L   Wheelan Sarah J SJ   Torbenson Michael S MS   O'Malley Bert W BW   Largaespada David A DA   Boeke Jef D JD  

Proceedings of the National Academy of Sciences of the United States of America 20120503 21


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 contr  ...[more]

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