Oncotarget

Research Papers:

miR-103 inhibits proliferation and sensitizes hemopoietic tumor cells for glucocorticoid-induced apoptosis

Shlomit Kfir-Erenfeld, Noa Haggiag, Moshe Biton, Polina Stepensky, Nathalie Assayag-Asherie and Eitan Yefenof _

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Oncotarget. 2017; 8:472-489. https://doi.org/10.18632/oncotarget.13447

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Abstract

Shlomit Kfir-Erenfeld1,*, Noa Haggiag1,*, Moshe Biton1, Polina Stepensky2, Nathalie Assayag-Asherie1,*, Eitan Yefenof1,*

1The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

2Pediatric Hemato-Oncology and Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

*These authors contributed equally to this work

Correspondence to:

Eitan Yefenof, email: [email protected]

Nathalie Assayag-Asherie, email: [email protected]

Keywords: glucocorticoid, miR-103, leukemia, apoptosis, proliferation

Received: June 01, 2016     Accepted: November 12, 2016     Published: November 18, 2016

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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