| Abstract: |
The heterogeneity and instability of human tumors hamper straightforward identification of cancer-causing mutations through genomic approaches alone. Herein we describe a mouse model of liver cancer initiated from progenitor cells harboring defined cancer-predisposing lesions. Genome-wide analyses of tumors in this mouse model and in human hepatocellular carcinomas revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses delineated cIAP1, a known inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. In the genetic context of their amplification, both cIAP1 and Yap accelerated tumorigenesis and were required to sustain rapid growth of amplicon-containing tumors. Furthermore, cIAP1 and Yap cooperated to promote tumorigenesis. Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes. © 2006 Elsevier Inc. All rights reserved. |
| Keywords: |
controlled study; unclassified drug; mutation; liver cell carcinoma; nonhuman; validation process; carcinoma, hepatocellular; liver neoplasms; animal cell; mouse; animals; mice; mice, knockout; animal tissue; cancer susceptibility; gene amplification; gene expression; animal experiment; animal model; transcription factor; cancer model; carcinogenesis; stem cell; nuclear proteins; oncogenes; cancer genetics; genome analysis; oncogene; species specificity; oligonucleotide array sequence analysis; gene identification; amplicon; inhibitor of apoptosis protein 1; inhibitor of apoptosis proteins; adaptor proteins, signal transducing; phosphoproteins; genomics; liver cancer; trans-activators; chromosome 11q; genes, p53; chromosome 9q; transcription factor yap; liver neoplasms, experimental
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