Abstract
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.
Highlights
Lung cancer is the leading cause of cancer deaths both in the United States and worldwide [1]
Confocal microscopic analyses revealed that irradiated non-small cell lung cancer (NSCLC) cells almost completely lost their ability to incorporate BrdU (Figure 1D), confirming that they were in the state of permanent cell cycle arrest, a characteristic feature of cellular senescence
Immunoblotting assays indicated that the expression levels of p16 and p21 were increased significantly, whereas phosphorylated Rb (pRb) levels declined markedly in irradiated NSCLC cells compared with non-irradiated control cells (Figure 1E)
Summary
Lung cancer is the leading cause of cancer deaths both in the United States and worldwide [1]. Even with current advanced treatment, the 5-year overall survival rate is less than 16% and has not changed appreciably over many decades [1, 2]. This highly unsatisfactory clinical outcome emphasizes an urgent need for the development of novel therapeutic approaches to more effectively manage this deadly disease. Our recent studies have demonstrated that activation of p53 www.impactjournals.com/oncotarget by Nutilin-3 sensitizes NSCLC cells to radiation by enhancing IR-induced senescence [3], suggesting that pharmacological promotion of senescence induction can be exploited as a novel and effective therapeutic approach to improve the efficacy of lung cancer radiotherapy
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