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MicroRNA-31 modulates tumour sensitivity to radiation in oesophageal adenocarcinoma

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Abstract

Chemoradiation therapy (CRT) prior to surgery is increasingly the standard of care for locally advanced oesophageal cancer. Radiation therapy is important for local tumour control; however, tumour resistance to radiation is a substantial clinical problem. The mechanism(s) of radioresistance are still poorly understood, however, mounting evidence supports a role for microRNA (miRNA) in modulating key cellular pathways mediating response to radiation. Global miRNA profiling of an established isogenic model of radioresistance in oesophageal adenocarcinoma demonstrated a significant downregulation of miR-31 in radioresistant cells, both basally and in response to radiation. Ectopic re-expression of miR-31 significantly re-sensitised radioresistant cells to radiation. miR-31 was demonstrated to alter the expression of 13 genes involved in DNA repair, which is a critical cellular defence against radiation-induced DNA damage. In oesophageal tumours, miR-31 expression was significantly reduced in patients demonstrating poor histomorphologic response to neoadjuvant CRT, whilst expression of the miR-31-regulated DNA repair genes was significantly increased. Our data suggest a possible mechanism for resistance to CRT, potentially via enhanced DNA repair. This study demonstrates, for the first time, a role for miR-31 in modulating radioresistance and highlights the need for further study investigating the potential role of miR-31 as both a predictive marker of response and a novel therapeutic agent with which to enhance the efficacy of radiation therapy.

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Acknowledgements

The authors thank Dr. Anthony Davies and Mr. Connla Edwards for assistance with high content screening analysis. This work was supported by the Irish Cancer Society and the C.R.O.S.S. Foundation (CHY 389874) at St. James’s Hospital. SGM is supported by an Irish Cancer Society Research Fellowship, CRF10MAH.

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There is no conflict of interest to disclose.

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Authors and Affiliations

  1. Department of Surgery, Trinity College Dublin, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland

    Niamh Lynam-Lennon, John V. Reynolds, Graham P. Pidgeon & Stephen G. Maher

  2. Division of Radiation Therapy, Trinity College Dublin, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland

    Laure Marignol

  3. Department of Histopathology, Trinity College Dublin, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland

    Orla M. Sheils

Authors
  1. Niamh Lynam-Lennon
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  2. John V. Reynolds
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  3. Laure Marignol
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  4. Orla M. Sheils
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  5. Graham P. Pidgeon
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  6. Stephen G. Maher
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Corresponding author

Correspondence to John V. Reynolds.

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Lynam-Lennon, N., Reynolds, J.V., Marignol, L. et al. MicroRNA-31 modulates tumour sensitivity to radiation in oesophageal adenocarcinoma. J Mol Med 90, 1449–1458 (2012). https://doi.org/10.1007/s00109-012-0924-x

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  • DOI: https://doi.org/10.1007/s00109-012-0924-x

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