Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma

X. Li, Y. Liu, K.J. Granberg, Q. Wang, L.M. Moore, P. Ji, J. Gumin, E Sulman, G.A. Calin, H. Haapasalo, M. Nykter, I. Shmulevich, G Fuller, F.F. Lang, W. Zhang

Research output: Contribution to journalArticleScientificpeer-review

62 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1619-28
Number of pages10
JournalOncogene
Volume34
Issue number13
DOIs
Publication statusPublished - 2015
Publication typeA1 Journal article-refereed

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