Abstract
BackgroundAn increasing number of studies have recently reported that microRNAs packaged in exosomes contribute to multiple biological processes such as cancer progression; however, little is known about their role in the development of radiation-induced bystander effects.MethodsThe exosomes were isolated from the culture medium of BEP2D cells with or without γ-ray irradiation by ultracentrifugation. To monitor DNA damage and repair efficiency, the DNA double-strand break biomarker 53BP1 foci, comet, micronuclei, expression of DNA repair genes and NHEJ repair activity were detected. The miR-1246 targeting sequence of the DNA ligase 4 (LIG4) mRNA 3′UTR was assessed by luciferase reporter vectors.ResultsmiR-1246 was increased in exosomes secreted from 2 Gy-irradiated BEP2D cells and inhibited the proliferation of nonirradiated cells. The miR-1246 mimic, exosomes from irradiated cells, and radiation-conditioned cell culture medium increased the yields of 53BP1 foci, comet tail and micronuclei in nonirradiated cells, and decreased NHEJ efficiency. miR-1246 downregulated LIG4 expression by directly targeting its 3′UTR.ConclusionsOur findings demonstrate that miR-1246 packaged in exosomes could act as a transfer messenger and contribute to DNA damage by directly repressing the LIG4 gene. Exosomal miR-1246 may be a critical predictor of and player in radiation-induced bystander DNA damage.
Highlights
Ionising radiation (IR), a double-edged sword used in diagnostic and medical therapeutic implements, is known to cause damage to normal tissue and cellular genomic instability, i.e., chromosomal aberrations.[1]
To further explore the biological function of miR-1246 packaged in exosomes in radiation-induced bystander effects (RIBEs), we performed a series of investigations on DNA damage effects of exosomal miR1246, Radiation conditioned cell culture medium (RCCM) and miRNA-1246 in BEF2D cells and HEK-293T cells
Our results indicated that following irradiation, miR-1246 expression was increased in exosomes and miR-1246 mimic inhibited cell proliferation and colony formation
Summary
Ionising radiation (IR), a double-edged sword used in diagnostic and medical therapeutic implements, is known to cause damage to normal tissue and cellular genomic instability, i.e., chromosomal aberrations.[1]. To monitor DNA damage and repair efficiency, the DNA double-strand break biomarker 53BP1 foci, comet, micronuclei, expression of DNA repair genes and NHEJ repair activity were detected. The miR-1246 targeting sequence of the DNA ligase 4 (LIG4) mRNA 3′UTR was assessed by luciferase reporter vectors. RESULTS: miR-1246 was increased in exosomes secreted from 2 Gy-irradiated BEP2D cells and inhibited the proliferation of nonirradiated cells. The miR-1246 mimic, exosomes from irradiated cells, and radiation-conditioned cell culture medium increased the yields of 53BP1 foci, comet tail and micronuclei in nonirradiated cells, and decreased NHEJ efficiency. MiR-1246 downregulated LIG4 expression by directly targeting its 3′UTR. CONCLUSIONS: Our findings demonstrate that miR-1246 packaged in exosomes could act as a transfer messenger and contribute to DNA damage by directly repressing the LIG4 gene. Exosomal miR-1246 may be a critical predictor of and player in radiationinduced bystander DNA damage
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