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cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation

Oncogene volume 36, pages 512–524 (2017)Cite this article

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Abstract

Elucidating the mechanisms involved in sensitizing radioresistant tumors to ionizing radiation (IR) treatments while minimizing injury to surrounding normal tissue is an important clinical goal. Due to their sequence-derived specificity and properties as gene regulators in IR-affected pathways, microRNAs (miRNAs) could serve as adjuvant therapeutic agents that alter cellular sensitivity to radiation treatment. To identify radiosensitizing miRNAs, we initially utilized the Caenorhabditis elegans vulval cell model, an in vivo system developed to study IR-dependent radiosensitivity as a measure of clonogenic cell death. We tested several candidate miRNA-deletion mutants post γ-irradiation and identified cel-mir-237 as a miRNA which when deleted caused animals to be more resistant to IR, whereas cel-mir-237 overexpressing strains were IR sensitive. In addition, wild-type animals downregulated cel-mir-237 levels post IR in a time-dependent manner. We identified jun-1 (JUN transcription factor homolog) as a novel target of cel-mir-237. Specifically, jun-1 transcript levels increased in wild-type animals post γ-irradiation, and loss of cel-mir-237 also resulted in higher jun-1 expression. As expected, loss of jun-1 resulted in IR sensitivity, similar to the phenotype of cel-mir-237 overexpressors. As miR-237 is the homolog of human miR-125, we validated our findings in MCF-7 and MDA-MB-231 breast cancer cell lines, which harbor lower hsa-miR-125b levels than normal human mammary epithelial cells (HMECs). Forced expression of hsa-miR-125b in these cells resulted in radiosensitivity, as seen by reduced clonogenic survival, enhanced apoptotic activity and enhanced senescence post IR. Finally, re-expression of c-JUN in MDA-MB-231 cells promoted radioresistance and abrogated miR-125-mediated radiosensitization. Our findings suggest that overexpression of cel-mir-237 and its homolog, hsa-miR-125b, functions as sensitizers to γ-irradiation in both a nematode in vivo model and breast cancer cells, and could potentially be utilized as an adjuvant therapeutic to enhance radiation sensitivity.

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Acknowledgements

We thank Geoffrey Lyon, Yale Cell Sorter Core Facility, for assistance with fluorescence-activated cell sorting and analysis, the Yale Cesium Irradiator Shared Resource for use of γ-irradiator, Valerie Horsley for use of imaging equipment, and to Shirin Bahmanyar for providing space and making equipment available for these studies. We thank Alan Jiao and Catherine O. Adams for critical reading of this manuscript. Nematode strains used in this work were provided by the C. elegans Genetics Center, which is funded by the National Institutes of Health National Center for Research Resources. This work was supported by grants to FJS and JBW from the NIH (R01 CA157749 and R01 CA131301). BDA was supported by a training grant (5T32 HG003198-10).

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Author notes

  1. C Metheetrairut

    Present address: 4Current address: Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.,

  2. J B Weidhaas

    Present address: 6Current address: Division of Molecular and Cellular Oncology, UCLA School of Medicine, Los Angeles, CA 90095, USA.,

  3. C Metheetrairut and B D Adams: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA

    C Metheetrairut, B D Adams & F J Slack

  2. Department of Pathology, Institute for RNA Medicine, BIDMC Cancer Center/Harvard Medical School, Boston, MA, USA

    B D Adams & F J Slack

  3. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA

    S Nallur & J B Weidhaas

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Metheetrairut, C., Adams, B., Nallur, S. et al. cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation. Oncogene 36, 512–524 (2017). https://doi.org/10.1038/onc.2016.222

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