TY - JOUR
T1 - A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer
AU - O'Donnell, Kathryn A.
AU - Keng, Vincent W.
AU - York, Brian
AU - Reineke, Erin L.
AU - Seo, Daekwan
AU - Fan, Danhua
AU - Silverstein, Kevin A.T.
AU - Schrum, Christina T.
AU - Xie, Wei Rose
AU - Mularoni, Loris
AU - Wheelan, Sarah J.
AU - Torbenson, Michael S.
AU - O'Malley, Bert W.
AU - Largaespada, David A.
AU - Boeke, Jef D.
PY - 2012/5/22
Y1 - 2012/5/22
N2 - 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.
AB - 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.
KW - Cancer gene identification
KW - Hepatocellular carcinoma
KW - Mouse models of cancer
KW - Myc oncogene
UR - http://www.scopus.com/inward/record.url?scp=84861432291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861432291&partnerID=8YFLogxK
U2 - 10.1073/pnas.1115433109
DO - 10.1073/pnas.1115433109
M3 - Article
C2 - 22556267
AN - SCOPUS:84861432291
SN - 0027-8424
VL - 109
SP - E1377-E1386
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -