Abstract：Objective: To explore the effect and mechanism of microRNA (miR) -221-3p in regulating ferroptosis to promote breast cancer metastasis. Methods: Human breast cancer cell line MCF-7 was cultured and transfected into MCF-7 cells using miR-221-3p mimic and mimic negative control (NC), real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the expression of miR-221-3p in transfected cells, the kit was used to determine the levels of bivalent iron ion (Fe2+), reactive oxygen species (ROS) and reduced glutathione (GSH) in transfected cells. MCF-7 cells were divided into control group, mimic NC group (transfected mimic NC), miR-221-3p mimic group (transfected miR-221-3p mimic), miR-221-3p mimic+Erastin group (transfected miR-221-3p mimic and treated with 10 μmoL/L Erastin). The proliferation activity and the number of migration and invasion of MCF-7 cells were respectively detected by cell counting kit-8 (CCK-8) assay and Transwell assay. Double-labeled immunofluorescence staining was applied to evaluate the expression of Nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4) in MCF-7 cells. Western blot was used to detect the protein expressions of NRF2, GPX4, solute carrier family 7 member 11 (SLC7A11) and ferritin light chain (FTL) in MCF-7 cells. Results: Compared with cells transfected with blank and mimic NC, cells transfected with miR-221-3p mimic had significantly up-regulated the proliferation activity of MCF-7 cells (P<0.05), elevated the numbers of migration and invasion of MCF-7 cells (P<0.05), decreased Fe2+ content (P<0.05), lower ROS level (P<0.05), increased GSH level (P<0.05), enhanced the fluorescence intensity of NRF2 and GPX4 (P<0.05), and up-regulated the proteins expressions of NRF2, GPX4, SLC7A11 and FTL (P<0.05). Compared with cells transfected with miR-221-3p mimic, cells transfected with miR-221-3p mimic+Erastin presented significantly down-regulated proliferation activity of MCF-7 cells, reduced the numbers of migration and invasion of MCF-7 cells (P<0.05), increased Fe2+ content (P<0.05), higher ROS level (P<0.05), decreased GSH level (P<0.05), weakened the fluorescence intensity of NRF2 and GPX4 (P<0.05), and down-regulated the proteins expressions of NRF2, GPX4, SLC7A11 and FTL (P<0.05). Conclusion: miR-221-3p can promote breast cancer metastasis by inhibiting ferroptosis, and the mechanism may be related to the activation of NRF2/GPX4 axis.
张倩, 马楠, 李琦, 丁伟, 张卫群. miR-221-3p通过NRF2/GPX4轴调节铁死亡促进乳腺癌细胞转移的分子机制研究[J]. 河北医学, 2025, 31(1): 22-28.
ZHANG Qian, MA Nan, LI Qi, et al. Molecular Mechanism of miR-221-3p in Inhibiting Ferroptosis to Promote Breast Cancer Metastasis via Activating NRF2/GPX4 Axis. HeBei Med, 2025, 31(1): 22-28.
[1] Newman L.Oncologic anthropology:Global variations in breast cancer risk,biology,and outcome[J].Surg Oncol,2023,128(6):959-966. [2] Yang Y,Zhang Y,Tang Y,et al.Anesthesia-related intervention for long-term survival and cancer recurrence following breast cancer surgery:a systematic review of prospective studies[J].PLoS One,2023,18(12):e0296158.. [3] Khan SA.Breast cancer risk reduction:current status and emerging trends to increase efficacy and reduce toxicity of preventive medication[J].Surg Oncol Clin N Am,2023,32(4):631-646. [4] Dos Santos AF,Fazeli G,Xavier da Silva TN,et al.Ferroptosis:mechanisms and implications for cancer development and therapy response[J].Trends Cell Biol,2023,33(12):1062-1076. [5] Zhou Q,Meng Y,Li D,et al.Ferroptosis in cancer:From molecular mechanisms to therapeutic strategies[J].Signal Transduct Target Ther,2024,9(1):55. [6] Chhichholiya Y,Singh HV,Singh S,et al.Genetic variations in tumor-suppressor miRNA-encoding genes and their target genes:focus on breast cancer development and possible therapeutic strategies[J].Clin Transl Oncol,2024,26(1):1-15. [7] Fang Y,Zhang Q,Chen Z,et al.Clinical significance and immune characteristics analysis of miR-221-3p and its key target genes related to epithelial-mesenchymal transition in breast cancer[J].Aging (Albany NY),2024,16(1):322-347. [8] Shao X,Zheng Y,Huang Y,et al.Hsa-miR-221-3p promotes proliferation and migration in HER2-positive breast cancer cells by targeting LASS2 and MBD2[J].Histol Histopathol,2022,37(11):1099-1112. [9] Koi Y,Yamamoto Y,Fukunaga S,et al.Assessment of the expression of microRNAs-221-3p,-146a-5p,-16-5p and BCL2 in oncocytic carcinoma of the breast:a case report[J].Oncol Lett,2023,26(6):535. [10] 刘庆,宋彩露,刘凌蕊,等.circ0000799经miR-1287-5p/GPX4轴调控铁死亡促进三阴乳腺癌脑转移[J].中南医学科学杂志,2024,52(1):6-11. [11] Zhao Y,Liu Z,Liu G,et al.Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1[J].Cell Metab,2023,35(10):1688-1703. [12] Li J,Li PT,Wu W,et al.POU2F2-mediated upregulation of lncRNA PTPRG-AS1 inhibits ferroptosis in breast cancer via miR-376c-3p/SLC7A11 axis[J].Epigenomics,2024,16(4):215-231. [13] Yan R,Xie E,Li Y,et al.The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis[J].Cell Res,2022,32(7):687-690. [14] 胡舒宁,邹心如,方译萱,等.Nrf2与铁死亡在肿瘤耐药中的研究进展[J].中国肺癌杂志,2023,26(10):765-773.
2025, Vol. 31 
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