MicroRNA regulation of ionizing radiation-induced premature senescence

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.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Busulfan
  • Cell Line
  • Cellular Senescence / genetics*
  • Cellular Senescence / radiation effects
  • DNA Damage
  • Down-Regulation
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Fibroblasts / radiation effects
  • Gene Silencing
  • Humans
  • MicroRNAs / analysis
  • MicroRNAs / physiology*
  • Microarray Analysis
  • Neoplasms / radiotherapy
  • Real-Time Polymerase Chain Reaction / methods
  • Up-Regulation


  • MicroRNAs
  • Busulfan