Journal
ONCOGENE
Volume 35, Issue 33, Pages 4407-4413Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.469
Keywords
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Funding
- European Research Council under the European Community's Seventh Framework Programme (FP7)/ERC [268626-EPINORC, HEALTH-F2-2010-258677-CURELUNG]
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2011-22803, PI13-01339, SAF2014-55000-R]
- Institute of Health Carlos III (ISCIII) [PI10/02992]
- Ministerio de Educacion, Ciencia e Innovacion [SAF2010-14935]
- Cellex Foundation
- National Cancer Center Research and Development Fund (NCC Biobank) [23 A-1]
- Health and Science Departments of the Catalan Government (Generalitat de Catalunya) AGAUR [2009SGR1315, 2014SGR633]
- ICREA Funding Source: Custom
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The introduction of new therapies against particular genetic mutations in non-small-cell lung cancer is a promising avenue for improving patient survival, but the target population is small. There is a need to discover new potential actionable genetic lesions, to which end, non-conventional cancer pathways, such as RNA editing, are worth exploring. Herein we show that the adenosine-to-inosine editing enzyme ADAR1 undergoes gene amplification in non-small cancer cell lines and primary tumors in association with higher levels of the corresponding mRNA and protein. From a growth and invasion standpoint, the depletion of ADAR1 expression in amplified cells reduces their tumorigenic potential in cell culture and mouse models, whereas its overexpression has the opposite effects. From a functional perspective, ADAR1 overexpression enhances the editing frequencies of target transcripts such as NEIL1 and miR-381. In the clinical setting, patients with early-stage lung cancer, but harboring ADAR1 gene amplification, have poor outcomes. Overall, our results indicate a role for ADAR1 as a lung cancer oncogene undergoing gene amplification-associated activation that affects downstream RNA editing patterns and patient prognosis.
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