Opperman Reid M, Maiti Sujit, Majumder Mousumi
Department of Biology, John R. Brodie Science Centre, Brandon University, 270 18th Street, Brandon, MB R7A6A9, Canada.
Int J Mol Sci. 2025 Sep 18;26(18):9103. doi: 10.3390/ijms26189103.
Oxidative stress has a dual role in breast cancer, promoting growth at moderate levels while causing cell death at higher levels, such as during therapeutic interventions that increase reactive oxygen species production. Oncogenic microRNAs miR-526b and miR-655 promote aggressive cancer traits-such as proliferation, migration, invasion, hypoxia response, cancer stem cell properties, and metastasis-via COX-2/EP4/PI3K pathways. These miRNAs and oxidative stress appear to engage in a self-amplifying loop, where miRNA overexpression increases ROS levels, and moderate oxidative stress, in turn, enhances miRNA expression-although the mechanisms are not yet fully understood. This study investigates how overexpressing miR-526b, miR-655, and COX-2 influences breast cancer cell responses to oxidative stress induced by HO. We examined cell viability, DNA damage, and transcriptomic changes in MCF7, MCF7-miR526b, MCF7-miR655, and MCF7-COX2 cell lines. Overexpression of COX-2 provided the most significant protection against oxidative stress, decreasing apoptosis and promoting cell cycle progression. Cells with miR-526b and miR-655 exhibited distinct yet overlapping stress responses, including decreased expression of DNA damage markers and alterations in p53 signaling. RNA-sequencing and network analyses identified hub genes involved in redox balance, immune, and metabolic pathways, which may have clinical significance (, , , ). Overall, these findings suggest that miR-526b, miR-655, and COX-2 play novel roles in promoting resistance to oxidative stress through transcriptional reprogramming in breast cancer; the identified markers could serve as potential biomarkers or therapeutic targets.
氧化应激在乳腺癌中具有双重作用，在中等水平时促进肿瘤生长，而在较高水平时导致细胞死亡，例如在增加活性氧产生的治疗干预过程中。致癌性微小RNA miR-526b和miR-655通过COX-2/EP4/PI3K途径促进侵袭性癌症特征，如增殖、迁移、侵袭、缺氧反应、癌症干细胞特性和转移。这些微小RNA与氧化应激似乎形成了一个自我放大的循环，微小RNA的过表达会增加活性氧水平，而适度的氧化应激反过来又会增强微小RNA的表达，尽管其机制尚未完全明确。本研究调查了miR-526b、miR-655和COX-2过表达如何影响乳腺癌细胞对过氧化氢诱导的氧化应激的反应。我们检测了MCF7、MCF7-miR526b、MCF7-miR655和MCF7-COX2细胞系中的细胞活力、DNA损伤和转录组变化。COX-2的过表达对氧化应激提供了最显著的保护作用，减少了细胞凋亡并促进了细胞周期进程。miR-526b和miR-655的细胞表现出独特但又重叠的应激反应，包括DNA损伤标志物表达降低和p53信号通路改变。RNA测序和网络分析确定了参与氧化还原平衡、免疫和代谢途径的枢纽基因，这些基因可能具有临床意义（，，，）。总体而言，这些发现表明，miR-526b、miR-655和COX-2在乳腺癌中通过转录重编程促进对氧化应激的抗性方面发挥了新的作用；所确定的标志物可作为潜在的生物标志物或治疗靶点。
