Proceedings of the National Academy of Sciences · 2012 · 66 citations · 50 references
MedicineGeneticsOncologyCancer GeneticsCarcinogenesisMolecular OncologyCancer GenomicsMyc Family OncogenesOncogene ActivationOncogene MutationsOncogenic Signaling PathwaysTumor Suppressor GenesCooperation Between MycLiver Progenitor CellsMyc ActivationMyc In Tumor ProgressionMyc-cooperating Oncogenic PathwaysOncogenic Driver MutationsOncogenic Myc SignalingTransposon Mutagenesis
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.
50
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Siân Jones, D. Williams Parsons, Jimmy Lin et al. · Science · 2008 · 4K citations · Full text