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Mir-301b-3p Targets Alx4 to Suppress Cisplatin Sensitivity in Breast Cancer through DNA Damage
Yan Yan1, Jianhong Xia1, Tingting Ma1
1Radiotherapy Department, The Second People's Hospital of Huai'an, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China.
Objective:
To elucidate how ALX Homeobox 4 (ALX4) modulates cisplatin sensitivity via DNA damage regulation in breast cancer (BC), this study explored the established role of mRNA-mediated DNA repair in driving chemoresistance.
Methods:
Integrated bioinformatics and molecular experiments identified ALX4 and miR-301b-3p expression patterns in BC cells. Potential binding sites between them were predicted and verified by dual-luciferase assays. Cellular experiments determined cisplatin IC50 via CCK-8 assays, while functional impacts of the miR-301b-3p/ALX4 axis on proliferation, apoptosis, and cisplatin-induced DNA damage were assessed using CCK-8, flow cytometry, alkaline comet assays, and western blot.
Results:
Our study identified downregulated ALX4 and upregulated miR-301b-3p in BC tissues. miR-301b-3p directly targeted ALX4, as confirmed by dual-luciferase assays. Overexpression of ALX4 inhibited BC cell proliferation, promoted apoptosis, enhanced cisplatin-induced DNA damage, and increased cisplatin sensitivity. Conversely, miR-301b-3p negatively regulated ALX4, thereby modulating DNA damage and cellular response to cisplatin.
Conclusion:
This study demonstrates that miR-301b-3p promotes BC proliferation and reduces cisplatin sensitivity by suppressing ALX4, a mechanism mediated through the regulation of DNA damage pathways. These findings offer new insights into cisplatin resistance and suggest potential therapeutic targets for overcoming chemoresistance in BC.
Insights
This study reveals that miR-301b-3p reduces cisplatin sensitivity in breast cancer (BC) by suppressing ALX4, impacting DNA damage repair. Understanding this mechanism offers new therapeutic targets for BC chemoresistance.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Chemoresistance in breast cancer (BC) is a significant clinical challenge.
- Messenger RNA (mRNA)-mediated DNA repair pathways are implicated in driving chemoresistance.
- The role of ALX Homeobox 4 (ALX4) in modulating DNA damage and cisplatin sensitivity requires elucidation.
Purpose of the Study:
- To investigate the regulatory role of ALX4 in cisplatin sensitivity within breast cancer.
- To explore the relationship between ALX4, miR-301b-3p, and DNA damage response pathways in BC.
- To identify potential therapeutic strategies targeting chemoresistance in BC.
Main Methods:
- Integrated bioinformatics and molecular experiments to analyze ALX4 and miR-301b-3p expression in BC.
- Dual-luciferase assays to confirm the targeting relationship between miR-301b-3p and ALX4.
- Cellular assays (CCK-8, flow cytometry, comet assays, western blot) to assess functional impacts on proliferation, apoptosis, and DNA damage.
Main Results:
- Downregulated ALX4 and upregulated miR-301b-3p were observed in BC tissues.
- miR-301b-3p was confirmed to directly target and suppress ALX4 expression.
- ALX4 overexpression enhanced cisplatin sensitivity by promoting DNA damage and apoptosis, while miR-301b-3p exerted opposite effects.
Conclusions:
- miR-301b-3p promotes BC proliferation and reduces cisplatin sensitivity by suppressing ALX4 via DNA damage pathway regulation.
- This miR-301b-3p/ALX4 axis represents a novel mechanism contributing to cisplatin resistance in breast cancer.
- Targeting this axis may offer a promising therapeutic strategy to overcome chemoresistance in BC.
