MiR-34a modulates ionizing radiation-induced senescence in lung cancer cells

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.

Macrophage migration inhibitory factor serves a pivotal role in�the regulation of radiation-induced cardiac senescencethrough rebalancing the microRNA-34a/sirtuin 1 signaling pathway

“…Among these, miR-34a has been implicated in cardiac-associated damage, particularly cardiac senescence (31). Researchers recently demonstrated that miR-34a was involved in modulating radiation-induced senescence, and that radiation-induced senescence was correlated with the upregulation of miR-34a expression (32). Accordingly, Figure 3.…”

Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells

“…In the non-small cell lung cancer (NSCLC) A549 cells, 2 Gy of radiation yielded ~ 20% of SA-β-Gal-positive cells, whereas 10 Gy generated the SA-β-Gal positivity in almost 80% of cells. This response is, however, also cell-type specific, as in the H460 line of NSCLC, which appeared to be more sensitive to the irradiation, which translated to the higher magnitude of senescence at analogical doses of the IR [103].…”

“…Significantly, an inhibition of glycolysis using dichloroacetate attenuated the ability of the tested cells to undergo IRdependent senescence [111]. In lung cancer cells, in turn, IR-induced senescence appeared to be regulated by miR-34a [103]. In glioma cells, the final status of cells subjected to IR (apoptosis vs. senescence) is determined by tumor suppressor, PTEN.…”

MicroRNA‐34a‐mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting

“…The expression of microRNA‐34a (miR‐34a) is suppressed in malignancies and cellular processes, such as cell differentiation, proliferation, and death . miR‐34a was shown to contribute to senescence regulation triggered via ionizing radiation in human non‐small cell lung cancer cells . miR‐34a also affects the migration and invasion of osteosarcoma cells, and miR‐34a exhaustion could enhance their expression pattern, resulting in osteosarcoma metastasis .…”