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miR-205 acts as a tumour radiosensitizer by targeting ZEB1 and Ubc13
Peijing Zhang1, Li Wang1, Cristian Rodriguez-Aguayo2
1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
Tumour cells associated with therapy resistance (radioresistance and drug resistance) are likely to give rise to local recurrence and distant metastatic relapse. Recent studies revealed microRNA (miRNA)-mediated regulation of metastasis and epithelial-mesenchymal transition; however, whether specific miRNAs regulate tumour radioresistance and can be exploited as radiosensitizing agents remains unclear. Here we find that miR-205 promotes radiosensitivity and is downregulated in radioresistant subpopulations of breast cancer cells, and that loss of miR-205 is highly associated with poor distant relapse-free survival in breast cancer patients. Notably, therapeutic delivery of miR-205 mimics via nanoliposomes can sensitize the tumour to radiation in a xenograft model. Mechanistically, radiation suppresses miR-205 expression through ataxia telangiectasia mutated (ATM) and zinc finger E-box binding homeobox 1 (ZEB1). Moreover, miR-205 inhibits DNA damage repair by targeting ZEB1 and the ubiquitin-conjugating enzyme Ubc13. These findings identify miR-205 as a radiosensitizing miRNA and reveal a new therapeutic strategy for radioresistant tumours.
Insights
MicroRNA-205 (miR-205) enhances cancer cell radiosensitivity by targeting DNA repair mechanisms. Restoring miR-205 levels offers a novel therapeutic strategy for overcoming radioresistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Therapy resistance, including radioresistance and drug resistance, in tumor cells contributes to cancer recurrence and metastasis.
- MicroRNAs (miRNAs) are implicated in regulating metastasis and epithelial-mesenchymal transition, but their role in tumor radioresistance is not fully understood.
Purpose of the Study:
- To investigate the role of specific miRNAs in regulating tumor radioresistance.
- To determine if miRNAs can be utilized as radiosensitizing agents.
- To explore miR-205 as a potential therapeutic target for overcoming radioresistance in breast cancer.
Main Methods:
- Analysis of miR-205 expression in radioresistant breast cancer cell subpopulations.
- Correlation of miR-205 levels with distant relapse-free survival in breast cancer patients.
- In vivo studies using nanoliposome-delivered miR-205 mimics in a xenograft model.
- Investigation of the molecular mechanisms involving ataxia telangiectasia mutated (ATM) and zinc finger E-box binding homeobox 1 (ZEB1) in miR-205 regulation by radiation.
- Assessment of miR-205's effect on DNA damage repair pathways by targeting ZEB1 and Ubc13.
Main Results:
- miR-205 promotes radiosensitivity and is downregulated in radioresistant breast cancer cells.
- Loss of miR-205 expression is associated with poor distant relapse-free survival in breast cancer patients.
- Therapeutic delivery of miR-205 mimics via nanoliposomes sensitized tumors to radiation in a xenograft model.
- Radiation suppresses miR-205 expression via ATM and ZEB1 pathways.
- miR-205 inhibits DNA damage repair by targeting ZEB1 and Ubc13.
Conclusions:
- miR-205 functions as a radiosensitizing miRNA in breast cancer.
- Downregulation of miR-205 contributes to radioresistance.
- miR-205 mimics delivered via nanoliposomes represent a potential therapeutic strategy for radioresistant tumors.
- Targeting the miR-205 pathway could overcome therapeutic resistance in cancer treatment.
