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  • Title: miR-103 inhibits proliferation and sensitizes hemopoietic tumor cells for glucocorticoid-induced apoptosis.
    Author: Kfir-Erenfeld S, Haggiag N, Biton M, Stepensky P, Assayag-Asherie N, Yefenof E.
    Journal: Oncotarget; 2017 Jan 03; 8(1):472-489. PubMed ID: 27888798.
    Abstract:
    Glucocorticoid (GC) hormones are an important ingredient of leukemia therapy since they are potent inducers of lymphoid cell apoptosis. However, the development of GC resistance remains an obstacle in GC-based treatment. In the present investigation we found that miR-103 is upregulated in GC-sensitive leukemia cells treated by the hormone. Transfection of GC resistant cells with miR-103 sensitized them to GC induced apoptosis (GCIA), while miR-103 sponging of GC sensitive cells rendered them partially resistant. miR-103 reduced the expression of cyclin dependent kinase (CDK2) and its cyclin E1 target, thereby leading to inhibition of cellular proliferation. miR-103 is encoded within the fifth intron of PANK3 gene. We demonstrate that the GC receptor (GR) upregulates miR-103 by direct interaction with GC response element (GRE) in the PANK3 enhancer. Consequently, miR-103 targets the c-Myc activators c-Myb and DVL1, thereby reducing c-Myc expression. Since c-Myc is a transcription factor of the miR-17~92a poly-cistron, all six miRNAs of the latter are also downregulated. Of these, miR-18a and miR-20a are involved in GCIA, as they target GR and BIM, respectively. Consequently, GR and BIM expression are elevated, thus advancing GCIA. Altogether, this study highlights miR-103 as a useful prognostic biomarker and drug for leukemia management in the future.
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