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Published on: November 2, 2020
An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer
Lars Zender1, Wen Xue, Johannes Zuber
1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Abstract:
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.
Insights
Researchers identified 13 tumor suppressor genes, including XPO4, crucial for cancer development using mouse models and RNA interference screens. This approach aids in functionally annotating the cancer genome.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Cancers exhibit significant heterogeneity with numerous passenger and driver mutations.
- Identifying novel tumor suppressor genes is critical for understanding cancer development and therapeutic strategies.
Purpose of the Study:
- To functionally identify tumor suppressor genes relevant to human cancer.
- To establish the feasibility of in vivo RNA interference (RNAi) screens for cancer gene discovery.
Main Methods:
- Compiled pools of short hairpin RNAs (shRNAs) targeting mouse orthologs of genes deleted in human hepatocellular carcinomas.
- Tested shRNA pools in a mosaic mouse model to assess their ability to promote tumorigenesis.
- Combined cancer genomics, RNA interference, and mosaic mouse models for functional gene annotation.
Main Results:
- Deletion-specific shRNA pools significantly accelerated hepatocarcinogenesis in mice.
- Identified and validated 13 tumor suppressor genes, with 12 previously unlinked to cancer.
- Discovered XPO4, a nuclear export protein, and its substrate EIF5A2, which is amplified in human tumors and promotes hepatocellular carcinoma.
Conclusions:
- In vivo RNAi screens are a feasible approach for discovering cancer-relevant genes.
- Combining genomic data with functional screens in mouse models effectively annotates the cancer genome.
- Novel tumor suppressor genes, like XPO4, offer potential new targets for cancer therapy.
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