A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions Journal Article
| Authors: | Xue, W.; Kitzing, T.; Roessler, S.; Zuber, J.; Krasnitz, A.; Schultz, N.; Revill, K.; Weissmueller, S.; Rappaport, A. R.; Simon, J.; Zhang, J.; Luo, W.; Hicks, J.; Zender, L.; Wang, X. W.; Powers, S.; Wigler, M.; Lowe, S. W. |
| Article Title: | A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions |
| 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, wetest 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. |
| Keywords: | cancer survival; controlled study; gene cluster; gene deletion; liver cell carcinoma; nonhuman; carcinoma, hepatocellular; mouse; animals; mice; animal tissue; mus; tumor volume; animal experiment; animal model; rna interference; in vivo study; cell line, tumor; chromosomes, human, pair 8; mice, inbred c57bl; cancer inhibition; tumor suppressor gene; gene expression regulation, neoplastic; liver; mice, nude; nucleotide sequence; murinae; cell line, transformed; stem cells; genomics; down regulation; chromosome 8p; tumor growth; chromosome deletion; genes, tumor suppressor; chromosome 17p; cancer genomics; monosomy; haploinsufficiency; liver neoplasms, experimental; chromosome 8p deletion; rnai screen |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 109 |
| Issue: | 21 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2012-05-22 |
| Start Page: | 8212 |
| End Page: | 8217 |
| Language: | English |
| DOI: | 10.1073/pnas.1206062109 |
| PROVIDER: | scopus |
| PMCID: | PMC3361457 |
| PUBMED: | 22566646 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 June 2012" - "CODEN: PNASA" - "Source: Scopus" |
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