An Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer

Zender, L., Xue, W., Zuber, J., Semighini, C. P., Krasnitz, A., Ma, B., Zender, P., Kubicka, S., Luk, J. M., Schirmacher, P., McCombie, W. R., Wigler, M. H., Hicks, J. B., Hannon, G. J., Powers, S., Lowe, S. W. (2008) An Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer. Cell, 135 (5). pp. 852-864. ISSN 0092-8674

URL: http://www.ncbi.nlm.nih.gov/pubmed/19012953
DOI: 10.1016/j.cell.2008.09.061

Abstract

Summary Cancers are highly heterogeneous and contain many passenger and driver mutations. To functionally identify tumor suppressor genes relevant to human cancer, we compiled pools of short hairpin RNAs (shRNAs) targeting the mouse orthologs of genes recurrently deleted in a series of human hepatocellular carcinomas and tested their ability to promote tumorigenesis in a mosaic mouse model. In contrast to randomly selected shRNA pools, many deletion-specific pools accelerated hepatocarcinogenesis in mice. Through further analysis, we identified and validated 13 tumor suppressor genes, 12 of which had not been linked to cancer before. One gene, XPO4, encodes a nuclear export protein whose substrate, EIF5A2, is amplified in human tumors, is required for proliferation of XPO4-deficient tumor cells, and promotes hepatocellular carcinoma in mice. Our results establish the feasibility of in vivo RNAi screens and illustrate how combining cancer genomics, RNA interference, and mosaic mouse models can facilitate the functional annotation of the cancer genome.

Item Type: Paper
Additional Information:
Uncontrolled Keywords: HUMDISEASE humdisease CELLCYCLE cell cycle
Subjects: diseases & disorders > cancer
Investigative techniques and equipment > assays
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > shRNA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > suppressor
CSHL Authors:
Communities: CSHL labs > Hannon lab
CSHL labs > Hicks lab
CSHL labs > Krasnitz lab
CSHL labs > Lowe lab
CSHL labs > McCombie lab
CSHL labs > Powers lab
CSHL labs > Wigler lab
Depositing User: CSHL Librarian
Date Deposited: 10 Apr 2012 14:34
Last Modified: 11 Apr 2013 19:21
PMCID: PMC2990916
Related URLs:
URI: http://repository.cshl.edu/id/eprint/25941

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