MiR-34a modulates ionizing radiation-induced senescence in lung cancer cells
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Xiaoyuan He1,*, Aimin Yang1,*, Daniel G. McDonald2, Ellen C. Riemer1, Kenneth N. Vanek2, Bradley A. Schulte1 and Gavin Y. Wang1,3
1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
2Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA
3Cancer Genes and Molecular Regulation Program of Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
*These authors have contributed equally to this work
Gavin Y. Wang, email: [email protected]
Keywords: microRNA-34a (miR-34a), ionizing radiation, non-small cell lung cancer, cellular senescence, c-Myc
Received: February 28, 2017 Accepted: June 09, 2017 Published: July 15, 2017
MicroRNAs (miRNAs) are a new class of gene expression regulators that have been implicated in tumorigenesis and modulation of the responses to cancer treatment including that of human non-small cell lung cancer (NSCLC). However, the role of miR-34a in ionizing radiation (IR)-induced senescence in NSCLC cells remains poorly understood. Here we report that IR-induced premature senescence correlates with upregulation of miR-34a expression in NSCLC cells. Ectopic overexpression of miR-34a by transfection with synthetic miR-34a mimics markedly enhances IR-induced senescence, whereas inhibition of miR-34a by transfection with a synthetic miR-34a inhibitor attenuates IR-induced senescence. Clonogenic assays reveal that treatment with miR-34a mimics augments IR-induced cell killing in human NSCLC cells. Mechanistically, we found that the senescence-promoting effect of miR-34a is associated with a dramatic down-regulation of c-Myc (Myc) expression, suggesting that miR-34a may promote IR-induced senescence via targeting Myc. In agreement with this suggestion, knockdown of Myc expression by RNAi recapitulates the senescence-promoting effect of miR-34a and enhances IR-induced cell killing in NSCLC cells. Collectively, these results demonstrate a previously unrecognized role for miR-34a in modulating IR-induced senescence in human NSCLC cells and suggest that pharmacological intervention of miR-34a expression may represent a new therapeutic strategy for improving the efficacy of lung cancer radiotherapy.
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