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Cellular and Molecular Biology

Exosome-packaged miR-1246 contributes to bystander DNA damage by targeting LIG4

British Journal of Cancervolume 119pages492502 (2018) | Download Citation

Abstract

Background

An 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.

Methods

The 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.

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 radiation-induced bystander DNA damage.

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Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.

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Acknowledgements

This study is supported by grants from National Key Basic Research Program (973 Program) of MOST, China (Grant No. 2015CB910601), the National Natural Science Foundation of China (Grant No. 31370843, 31500681), and the Natural Science foundation of Hunan Province(No.2016JJ2115).

Author contributions

R.-X.H. and P.-K.Z. contributed the study concept and critical design of this study. L.-J.M., M.S., Q.-H.H., H.G., X.-D.L., D.-F.X. and B.H. conducted the cell experiments. L.-J.M. and M.S. acquired, analysed and interpreted the data. R.-X.H., L.-J.M., M.S. fulfil the initial manuscript and P.-K.Z. critically reviewed and revised the final manuscript.

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Author notes

  1. Co-first authors: Li-Jun Mo, Man Song.

Affiliations

  1. Institute for Environmental Medicine and Radiation Health, the College of Public Health, University of South China, 421001, Hengyang, Hunan Province, P.R. China

    • Li-Jun Mo
    • , Qiao-Hua Huang
    •  & Bo Huang
  2. Beijing Key Laboratory for Radiobiology, Department of Radiation Biology, Beijing Institute of Radiation Medicine, 100850, Beijing, P.R. China

    • Li-Jun Mo
    • , Man Song
    • , Hua Guan
    • , Xiao-Dan Liu
    • , Da-Fei Xie
    •  & Ping-Kun Zhou
  3. Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, 410078, Changsha, Hunan Province, P.R. China

    • Rui-Xue Huang
  4. Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory, Guangzhou Medical University, 511436, Guangzhou, P.R. China

    • Ping-Kun Zhou

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The authors declare no competing interests.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding authors

Correspondence to Rui-Xue Huang or Ping-Kun Zhou.

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DOI

https://doi.org/10.1038/s41416-018-0192-9

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