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Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):839-48. doi: 10.1016/j.ijrobp.2010.09.048. Epub 2010 Nov 17.

MicroRNA regulation of ionizing radiation-induced premature senescence.

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  • 1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA. wangy@musc.edu

Abstract

PURPOSE:

MicroRNAs (miRNAs) have emerged as critical regulators of many cellular pathways. Ionizing radiation (IR) exposure causes DNA damage and induces premature senescence. However, the role of miRNAs in IR-induced senescence has not been well defined. Thus, the purpose of this study was to identify and characterize senescence-associated miRNAs (SA-miRNAs) and to investigate the role of SA-miRNAs in IR-induced senescence.

METHODS AND MATERIALS:

In human lung (WI-38) fibroblasts, premature senescence was induced either by IR or busulfan (BU) treatment, and replicative senescence was accomplished by serial passaging. MiRNA microarray were used to identify SA-miRNAs, and real-time reverse transcription (RT)-PCR validated the expression profiles of SA-miRNAs in various senescent cells. The role of SA-miRNAs in IR-induced senescence was characterized by knockdown of miRNA expression, using anti-miRNA oligonucleotides or by miRNA overexpression through the transfection of pre-miRNA mimics.

RESULTS:

We identified eight SA-miRNAs, four of which were up-regulated (miR-152, -410, -431, and -493) and four which were down-regulated (miR-155, -20a, -25, and -15a), that are differentially expressed in both prematurely senescent (induced by IR or BU) and replicatively senescent WI-38 cells. Validation of the expression of these SA-miRNAs indicated that down-regulation of miR-155, -20a, -25, and -15a is a characteristic miRNA expression signature of cellular senescence. Functional analyses revealed that knockdown of miR-155 or miR-20a, but not miR-25 or miR-15a, markedly enhanced IR-induced senescence, whereas ectopic overexpression of miR-155 or miR-20a significantly inhibited senescence induction. Furthermore, our studies indicate that miR-155 modulates IR-induced senescence by acting downstream of the p53 and p38 mitogen-activated protein kinase (MAPK) pathways and in part via regulating tumor protein 53-induced nuclear protein 1 (TP53INP1) expression.

CONCLUSION:

Our results suggest that SA-miRNAs are involved in the regulation of IR-induced senescence, so targeting these miRNAs may be a novel approach for modulating cellular response to radiation exposure.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21093163
[PubMed - indexed for MEDLINE]
PMCID:
PMC3056910
Free PMC Article
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