Exosome-mediated microRNA transfer plays a role in radiation-induced bystander effect

Abstract

Bystander effects can be induced through cellular communication between irradiated cells and non-irradiated cells. The signals that mediate this cellular communication, such as cytokines, reactive oxygen species, nitric oxide and even microRNAs, can be transferred between cells via gap junctions or extracellular medium. We have previously reported that miR-21, a well described DDR (DNA damage response) microRNA, is involved in radiation-induced bystander effects through a medium-mediated way. However, the mechanisms of the microRNA transfer have not been elucidated in details. In the present study, it was found that exosomes isolated from irradiated conditioned medium could induce bystander effects. Furthermore, we demonstrated plenty of evidences that miR-21, which is up-regulated as a result of mimic transfection or irradiation, can be transferred from donor or irradiated cells into extracellular medium and subsequently get access to the recipient or bystander cells through exosomes to induce bystander effects. Inhibiting the miR-21 expression in advance can offset the bystander effects to some extent. From all of these results, it can be concluded that the exosome-mediated microRNA transfer plays an important role in the radiation-induced bystander effects. These findings provide new insights into the functions of microRNAs and the cellular communication between the directly irradiated cells and the non-irradiated cells.

Exosomes are released by bystander cells exposed to radiation-induced biophoton signals: Reconciling the mechanisms mediating the bystander effect

“…Irradiation of a given cell can trigger the upregulation of specific miRNAs such as those involved in DNA damage response functions [32]. Through packaging of these miRNAs within vesicles such as exosomes, the miRNAs are easily exchanged intercelluarly and can subsequently elicit bystander effects in recipient cells.…”

Extracellular miR-1246 promotes lung cancer cell proliferation and enhances radioresistance by directly targeting DR5

“…A large number of studies have raised that the extracellular miRNAs may play an important role in regulating intercellular communication and thus have implications in tumor biology [13, 16, 29, 30, 36]. In addition, some evidences indicate that extracellular miRNAs are relevant to RIBE [24, 25]. However, there is no literature concerning the role of radiation-induced extracellular miRNAs in regulating cell radiosensitivity.…”

“…Numerous studies have confirmed that many kinds of diffusible signaling factors contribute to the generation of RIBE, including reactive oxygen species (ROS), reactive nitrogen species (RNS), cytochrome-c and cytokines [21–23]. Recently, it was reported that miR-663 and miR-21 were involved in the RIBE through a medium-mediated pathway [24, 25]. However, the characteristics of extracellular miRNA expressions responding to IR and the potential roles of miRNAs in regulating cell radiosensitivity are still largely unknown.…”

Extracellular Vesicles and Vascular Injury: New Insights for Radiation Exposure

“…Interestingly, transfection of miR-21 mimics into MRC-5 cells induced similar effects, suggesting a role for miR-21 in mediating RIBE. In a follow-up study, the same group demonstrated that exosomes isolated from irradiated CM could induce bystander effects by mediating miR-21 transfer from irradiated to bystander cells (149). Inhibition of miR-21 before irradiation blunted these effects, suggesting that exosome-mediated miR-21 transfer plays an important role in RIBE.…”