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

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, micr...

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Autores principales: Metheetrairut, Chanatip, Adams, Brian D., Nallur, Sunitha, Weidhaas, Joanne B., Slack, Frank J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173455/
https://www.ncbi.nlm.nih.gov/pubmed/27321180
http://dx.doi.org/10.1038/onc.2016.222
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author Metheetrairut, Chanatip
Adams, Brian D.
Nallur, Sunitha
Weidhaas, Joanne B.
Slack, Frank J.
author_facet Metheetrairut, Chanatip
Adams, Brian D.
Nallur, Sunitha
Weidhaas, Joanne B.
Slack, Frank J.
author_sort Metheetrairut, Chanatip
collection PubMed
description 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 C. 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, while cel-mir-237 overexpressing strains were IR-sensitive. Additionally, 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. Since miR-237 is the homologue 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 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 radio-resistance and abrogated miR-125-mediated radio-sensitization. Our findings suggest that overexpression of cel-mir-237 and its homologue, 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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spelling pubmed-51734552017-01-27 cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation Metheetrairut, Chanatip Adams, Brian D. Nallur, Sunitha Weidhaas, Joanne B. Slack, Frank J. Oncogene Article 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 C. 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, while cel-mir-237 overexpressing strains were IR-sensitive. Additionally, 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. Since miR-237 is the homologue 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 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 radio-resistance and abrogated miR-125-mediated radio-sensitization. Our findings suggest that overexpression of cel-mir-237 and its homologue, 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. 2016-06-20 2017-01-26 /pmc/articles/PMC5173455/ /pubmed/27321180 http://dx.doi.org/10.1038/onc.2016.222 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Metheetrairut, Chanatip
Adams, Brian D.
Nallur, Sunitha
Weidhaas, Joanne B.
Slack, Frank J.
cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation
title cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation
title_full cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation
title_fullStr cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation
title_full_unstemmed cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation
title_short cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation
title_sort cel-mir-237 and its homologue, hsa-mir-125b, modulate the cellular response to ionizing radiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173455/
https://www.ncbi.nlm.nih.gov/pubmed/27321180
http://dx.doi.org/10.1038/onc.2016.222
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