Related Experiment Video
Updated: Mar 19, 2026
Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation
C Metheetrairut1, B D Adams1,2, S Nallur3
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
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.
Insights
Overexpressing microRNAs (miRNAs), specifically cel-mir-237 and its human homolog hsa-miR-125b, can sensitize radioresistant tumors to ionizing radiation (IR). This approach enhances radiation therapy effectiveness by targeting the JUN transcription factor pathway.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- MicroRNAs (miRNAs) regulate gene expression and are implicated in cellular responses to ionizing radiation (IR).
- Identifying miRNAs that sensitize radioresistant tumors to IR is crucial for improving cancer treatment outcomes.
- Minimizing damage to normal tissues during radiation therapy is a significant clinical challenge.
Purpose of the Study:
- To identify microRNAs (miRNAs) that can sensitize radioresistant cells to ionizing radiation (IR).
- To elucidate the molecular mechanisms underlying miRNA-mediated radiosensitization.
- To validate the potential of specific miRNAs as adjuvant therapeutic agents in breast cancer.
Main Methods:
- Utilized the Caenorhabditis elegans vulval cell model to screen for radiosensitizing miRNAs.
- Identified and characterized the role of cel-mir-237 and its target jun-1 (JUN transcription factor homolog).
- Validated findings in human breast cancer cell lines (MCF-7, MDA-MB-231) and normal human mammary epithelial cells (HMECs) using hsa-miR-125b and c-JUN.
Main Results:
- Deletion of cel-mir-237 in C. elegans conferred radioresistance, while overexpression led to radiosensitivity.
- cel-mir-237 directly targets jun-1, and loss of jun-1 resulted in IR sensitivity.
- Overexpression of human hsa-miR-125b in breast cancer cells induced radiosensitivity, reduced clonogenic survival, and enhanced apoptosis and senescence post-IR.
- Re-expression of c-JUN abrogated miR-125-mediated radiosensitization.
Conclusions:
- Overexpression of cel-mir-237 and hsa-miR-125b sensitizes cells to gamma irradiation in vivo and in vitro.
- The cel-mir-237/jun-1 and hsa-miR-125b/c-JUN pathways are key regulators of radiosensitivity.
- These miRNAs hold potential as adjuvant therapies to enhance the efficacy of radiation treatments for radioresistant cancers.
