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MiR-199a-3p enhances breast cancer cell sensitivity to cisplatin by downregulating TFAM (TFAM)
Xuelong Fan1, Shangcheng Zhou2, Miao Zheng3
1Medicine College of Hunan Normal University, Changsha, Hunan, 410006, China; School of Public Health, Central South University, Changsha, Hunan, 410078, China.
Abstract:
Chemotherapy resistance is the major obstacle to the effective therapy of cancer. While the mechanism of chemotherapy resistance is still not fully understood. Increasing evidences demonstrated that microRNAs (miRNAs) may have a crucial function in chemotherapy resistance through modulating intracellular pathways. MiR-199a has been shown to be involved in multiple malignancy-related processes, although the precise mechanism is unclear at present. In this study, we found that the expression level of miR-199a-3p was lower in cisplatin (DDP) resistant breast cancer MDA-MB-231/DDP cells compared with parental DDP-sensitive cells. Inhibition of miR-199a-3p in MDA-MB-231 cells significantly attenuated DDP-induced apoptosis and anti-proliferative effects, while overexpression of miR-199a-3p in MDA-MB-231/DDP cells increased the sensitivity to DDP. Moreover, expression levels of mitochondrial transcription factor A (TFAM) were modulated by miR-199a-3p. The luciferase reporter assay indicated that TFAM may be the target gene of miR-199a. Knocking down of TFAM could partially reverse DDP resistance in MDA-MB-231 cells induced by miR-199a-3p inhibition, while TFAM overexpression could partially restore miR-199a-3p-induced chemo-sensitivity of MDA-MB-231/DDP cells to DDP. These results show that miR-199a-3p is able to attenuate cisplatin resistance in breast cancer cells through inhibiting TFAM expression.
Insights
MicroRNA miR-199a-3p can overcome cisplatin resistance in breast cancer. Lower miR-199a-3p levels promote resistance by increasing mitochondrial transcription factor A (TFAM), while higher levels enhance sensitivity.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Chemotherapy resistance is a significant challenge in cancer treatment.
- MicroRNAs (miRNAs) play a role in modulating cellular pathways involved in drug resistance.
- The specific mechanisms of miRNA involvement in chemotherapy resistance require further elucidation.
Purpose of the Study:
- To investigate the role of miR-199a-3p in cisplatin resistance in breast cancer.
- To identify the molecular targets of miR-199a-3p involved in chemoresistance.
- To explore the therapeutic potential of modulating miR-199a-3p in overcoming drug resistance.
Main Methods:
- Comparison of miR-199a-3p expression in cisplatin-sensitive and resistant breast cancer cell lines.
- In vitro functional assays including apoptosis and proliferation studies.
- Luciferase reporter assays to validate target gene interactions.
- Gene knockdown and overexpression studies to assess functional effects.
Main Results:
- miR-199a-3p expression was significantly lower in cisplatin-resistant breast cancer cells.
- Inhibition of miR-199a-3p reduced cisplatin-induced apoptosis and proliferation.
- Overexpression of miR-199a-3p increased sensitivity to cisplatin in resistant cells.
- miR-199a-3p directly targets and inhibits mitochondrial transcription factor A (TFAM).
- Modulating TFAM partially reversed the effects of miR-199a-3p on cisplatin resistance.
Conclusions:
- miR-199a-3p plays a critical role in attenuating cisplatin resistance in breast cancer.
- The miR-199a-3p/TFAM axis is a key regulator of chemoresistance.
- Targeting miR-199a-3p or its downstream effectors like TFAM may offer a therapeutic strategy to overcome chemotherapy resistance.
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