Attenuated adenosine-to-inosine editing of microRNA-376a promotes invasiveness of glioblastoma cells
2012
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- Autor(en) / Beteiligte
- Titel
- Attenuated adenosine-to-inosine editing of microRNA-376a promotes invasiveness of glioblastoma cells
- Ist Teil von
- The Journal of clinical investigation, 2012-11, Vol.122 (11), p.4059-4076
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2012
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- In the human brain, microRNAs (miRNAs) from the microRNA-376 (miR-376) cluster undergo programmed "seed" sequence modifications by adenosine-to-inosine (A-to-I) editing. Emerging evidence suggests a link between impaired A-to-I editing and cancer, particularly in high-grade gliomas. We hypothesized that disruption of A-to-I editing alters expression of genes regulating glioma tumor phenotypes. By sequencing the miR-376 cluster, we show that the overall miRNA editing frequencies were reduced in human gliomas. Specifically in high-grade gliomas, miR-376a* accumulated entirely in an unedited form. Clinically, a significant correlation was found between accumulation of unedited miR-376a* and the extent of invasive tumor spread as measured by magnetic resonance imaging of patient brains. Using both in vitro and orthotopic xenograft mouse models, we demonstrated that the unedited miR-376a* promoted glioma cell migration and invasion, while the edited miR-376a* suppressed these features. The effects of the unedited miR-376a* were mediated by its sequence-dependent ability to target RAP2A and concomitant inability to target AMFR. Thus, the tumor-dependent introduction of a single base difference in the miR-376a* sequence dramatically alters the selection of its target genes and redirects its function from inhibiting to promoting glioma cell invasion. These findings uncover a new mechanism of miRNA deregulation and identify unedited miR-376a* as a potential therapeutic target in glioblastoma cells.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/jci62925Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3484441
- Format
- –
- Schlagworte
- Adenosine, Adenosine - genetics, Adenosine - metabolism, Animal models, Animals, Biomedical research, Brain, Brain cancer, Brain Neoplasms - genetics, Brain Neoplasms - metabolism, Brain Neoplasms - pathology, Brain tumors, Cancer invasiveness, Care and treatment, Cell adhesion & migration, Cell Line, Tumor, Cell migration, Cloning, Development and progression, Editing, Female, Genes, Glioblastoma - genetics, Glioblastoma - metabolism, Glioblastoma - pathology, glioblastoma cells, Glioblastoma multiforme, Glioma, Glioma cells, Humans, Inosine - genetics, Inosine - metabolism, Invasiveness, Magnetic resonance imaging, Male, Mice, Mice, Inbred BALB C, Mice, Nude, MicroRNA, MicroRNAs, MicroRNAs - genetics, MicroRNAs - metabolism, miRNA, Neoplasm Invasiveness, Neoplasm Transplantation, Neuroimaging, Properties, RNA Editing, RNA, Neoplasm - genetics, RNA, Neoplasm - metabolism, Seeds, Sequence Analysis, RNA, Transplantation, Heterologous, Tumors, Xenografts