期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 21, 页码 8212-8217出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206062109
关键词
cancer genomics; chromosome 8p deletion; RNAi screen
资金
- German Research Foundation [KI1605/1-1]
- American Association for Cancer Research
- National Cancer Institute
- Cancer Target Discovery and Development consortium
- Don Monti Memorial Research Foundation
- Department of the Army [W81XWH04-1-0477]
- Breast Cancer Research Foundation
The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a two-hit mechanismin 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.
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