MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets EGFR, CDK6 and Bcl-xL, whereas miR-491-3p targets IGFBP2 and CDK6. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary Ink4a-Arf-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore, MIR-491 is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.
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We appreciate Xinna Zhang at the MicroRNA Core Facility for help with miRNA hybridization experiments, Zhimin Lu at the Department of Neuro-Oncology-Research for helpful comments, and Kathryn L Hale at the Department of Scientific Publications at MD Anderson Cancer Center for manuscript editing. This work was supported by grants from the National Institutes of Health (CA098503 to WZ and IS, CA141432 and CA143835 to WZ and CA115729 and CA127001 to FFL), IVY, Elias and Broach Foundations, the Gene Pennebaker Brain Cancer Fund, and the Academy of Finland (grant 259038 to KG); Xia Li was supported by a fellowship from The Fourth Military Medical University (4138C4IA1Z). Lynette Moore was supported by a fellowship from the American Cancer Society.
The authors declare no conflict of interest.
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Li, X., Liu, Y., Granberg, K. et al. Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma. Oncogene 34, 1619–1628 (2015). https://doi.org/10.1038/onc.2014.98
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