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An Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer
Open accessAbstract
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 harpin 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.
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Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Self-citationColorectal cancer and genetic alterations in the Wnt pathway
Segditsas, S., & Tomlinson, I. (2006) · Oncogene · doi:10.1038/sj.onc.1210059 · Cited by 591
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High-throughput functional genomics using CRISPR-Cas9
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Self-citationGenome-wide CRISPR Screen in a Mouse Model of Tumor Growth and Metastasis
Chen, S., Sanjana, N. E., Zheng, K., Shalem, O., Lee, K., Shi, X., Scott, D. A., Song, J., Pan, J. Q., Weissleder, R., et al. (2015) · Cell · doi:10.1016/j.cell.2015.02.038 · Cited by 862
Metadata
- Authors
- Zender, L., Xue, W., Zuber, J., Semighini, C. P., Krasnitz, A., Ma, B., Zender, P., Kubicka, S., Luk, J. M., Schirmacher, P., Richard McCombie, W., Wigler, M., Hicks, J., Hannon, G. J., Powers, S., & Lowe, S. W.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 135
- Issue
- 5
- Pages
- 852-864
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2167005345
- Cited by
- 428
- References
- 2
- FWCI
- 9.80
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Zender, L., Xue, W., Zuber, J., Semighini, C. P., Krasnitz, A., Ma, B., Zender, P., Kubicka, S., Luk, J. M., Schirmacher, P., Richard McCombie, W., Wigler, M., Hicks, J., Hannon, G. J., Powers, S., & Lowe, S. W. (2008). An Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer. Cell. https://doi.org/10.1016/j.cell.2008.09.061
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