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- Title
Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells.
- Authors
Choudhury, Yukti; Felix Chang Tay; Dang Hoang Lam; Sandanaraj, Edwin; Carol Tang; Beng-Ti Ang; Shu Wang
- Abstract
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 dis-ruption 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. Spe-cifically in high-grade gliomas, miR-376a* accumulated entirely in an unedited form. Clinically, a significant correlation was found between accumulation of unedited mi R-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.
- Subjects
MICRORNA; PROMOTERS (Genetics); CANCER cells; NUCLEOTIDE sequence; GENE expression; GLIOMAS; GENETIC regulation
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 11, p4059
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI62925