TY - JOUR
T1 - MiR-103 inhibits proliferation and sensitizes hemopoietic tumor cells for glucocorticoid-induced apoptosis
AU - Kfir-Erenfeld, Shlomit
AU - Haggiag, Noa
AU - Biton, Moshe
AU - Stepensky, Polina
AU - Assayag-Asherie, Nathalie
AU - Yefenof, Eitan
N1 - We wish to thank Dr. Smadar Avigad for providing us with ALL samples, to Professor Noam Shomron for the Deep Sequencing service and Professors Ofer Mandelboim, Hanna Margalith and Yehudith Bergman for their advice. This study was supported by grants from The German Israel Foundation (GIF), Concern Foundation and Kamin. S.K.E is supported by an ICRF fellowship and a Walwish grant. Authors’ contributions: S.KE. performed the experiments and wrote the paper. N.H. performed the experiments. M.B. designed the plasmids. P.S. collected and provided clinical samples and data. N.A.A. performed the experiments and wrote the paper. E.Y. supervised the study and wrote the paper.
PY - 2017/1/3
Y1 - 2017/1/3
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Glucocorticoid
KW - Leukemia
KW - MiR-103
KW - Proliferation
UR - http://www.scopus.com/inward/record.url?scp=85009487434&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.13447
DO - 10.18632/oncotarget.13447
M3 - مقالة
C2 - 27888798
SN - 1949-2553
VL - 8
SP - 472
EP - 489
JO - Oncotarget
JF - Oncotarget
IS - 1
ER -
