A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions.
Proc Natl Acad Sci U S A
; 109(21): 8212-7, 2012 May 22.
Article
em En
| MEDLINE
| ID: mdl-22566646
ABSTRACT
The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a "two-hit" mechanism in the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large cancer-associated deletions can produce phenotypes distinct from those arising through loss of a single TSG, and as such should be considered and studied as distinct mutational events.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Genes Supressores de Tumor
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Deleção de Genes
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Carcinoma Hepatocelular
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Genômica
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Neoplasias Hepáticas Experimentais
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Monossomia
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos