Intronic miRNA-641 controls its host Gene's pathway PI3K/AKT and this relationship is dysfunctional in glioblastoma multiforme

• Published in: Biochemical and biophysical research communications 2017-08, Vol.489 (4), p.477-483
• Main Authors: Hinske, Ludwig Christian, Heyn, Jens, Hübner, Max, Rink, Jessica, Hirschberger, Simon, Kreth, Simone
• Format: Article
• Language: English
• Subjects: Apoptosis; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma multiforme; Humans; Intronic miRNA; MicroRNAs - genetics; MicroRNAs - metabolism; mir-641; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; PI3K/AKT pathway; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Tumor Cells, Cultured
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.05.175

MicroRNAs have established their role as important regulators of the epigenome. A considerable number of human miRNA genes are found in intronic regions of protein-coding host genes, in many cases adopting their regulatory circuitry. However, emerging evidence foreshadows an unprecedented importance for this relationship: Intronic miRNAs may protect the cell from overactivation of the respective host pathway, a setting that may trigger tumor development. AKT2 is a well-known proto-oncogene central to the PI3K/AKT pathway. This pathway is known to promote tumor growth and survival, especially in glioblastoma. Its intronic miRNA, hsa-miR-641, is scarcely investigated, however. We hypothesized that miR-641 regulates its host AKT2 and that this regulation may become dysfunctional in glioblastoma. We found that indeed miR-641 expression differs significantly between GBM tissue and normal brain samples, and that transfection of glioma cells with miR-641 antagonizes the PI3K/AKT pathway. Combining clinical samples, cell cultures, and biomolecular methods, we could show that miR-641 doesn't affect AKT2's expression levels, but down-regulates kinases that are necessary for AKT2-activation, thereby affecting its functional state. We also identified NFAT5 as a miR-641 regulated central factor to trigger the expression of these kinases and subsequently activate AKT2. In summary, our study is the first that draws a connecting line between the proto-oncogene AKT2 and its intronic miRNA miR-641 with implication for glioblastoma development. •Intronic miR-641 functionally antagonizes activation of its host gene AKT2.•miR-641 directly targets the AKT2 activating kinases PIK3R3 and MAPKAP1.•miR-641 indirectly regulates the AKT2-activating kinases PIK3R3 and PDK2 via NFAT5.•miR-641 triggers apoptosis in GBM cells when its expression is restored.•Human GBM samples show a distorted relationship between miR-641 and AKT2.