Abstract
Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1α expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1α represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1α-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1α-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1α-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1α regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action.
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Abbreviations
- AML:
-
acute myeloid leukemia
- CBMC:
-
cord blood mononuclear cells
- CDK:
-
cyclin-dependent kinase
- C/EBPα:
-
CCAAT/enhancer binding protein alpha
- DLBCLs:
-
diffuse large B-cell lymphomas
- HIF-1:
-
hypoxia-inducible factor 1
- HREs:
-
hypoxia-responsive elements
- PHD:
-
prolyl hydroxylase
- STAT3:
-
signal transducer and activator of transcription 3
- UTR:
-
untranslated region
- VEGF:
-
vascular endothelial growth factor
- VHL:
-
von Hippel-Lindau
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Acknowledgements
This study was supported by National Key Program (973) for Basic Research of China (2009CB918404) and National Science Foundation of China (81170505, 81172521, and 30971107). Additionally, we also gain support from ‘Shu Guang’ project by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (09SG18), Foundation for the author of National Excellent Doctoral Dissertation of China and a grant from Science and Technology Committee of Shanghai (10QA1404000). We would like to thank Dr. Danica Chen, Yufei Liu, Mary Mohrin, and Livia Wilz of the University of California, Berkeley for the grammar revision of this manuscript. We also thank the LC SCIENCES and Genminix Company for the technical assistances.
Author Contributions
MH designed the research, performed most experiments, analyzed the data and drafted the article. QW, QY, and Yl performed some experiments to evaluate differentiation. Yl, JT, and CZ performed some experiments on the miRNAs expression analyses. CD and DH performed some experiments of animal model construction. TT provided the hybridoma TM-β1 cell line. GC and QZ conceived and designed the study, critically revised the manuscript for important intellectual content, and approved the version to be published.
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He, M., Wang, QY., Yin, QQ. et al. HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation. Cell Death Differ 20, 408–418 (2013). https://doi.org/10.1038/cdd.2012.130
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DOI: https://doi.org/10.1038/cdd.2012.130
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