Seven Didem, Tecimel Didem, Özbey Utku, Kızılilsoley Nehir, Nikerel Emrah, Dalan Altay Burak, Türe Uğur, Bayrak Ömer Faruk
Department of Medical Genetics, School of Medicine, Yeditepe University, İstanbul, 34755, Turkey.
Faculty of Engineering, Genetics and Bioengineering Department, Yeditepe University, İstanbul, 34755, Turkey.
Mol Biol Rep. 2025 Jan 24;52(1):157. doi: 10.1007/s11033-025-10239-2.
Chordoma, characterized as a slow growing yet locally invasive and destructive bone tumor mainly emerging in the sacrum and clivus, presents a unique challenge due to its rarity, hampering the development of effective treatment strategies. Comprehensive understanding of tumor biology is crucial to suggest novel treatment modalities. Reactive oxygen species (ROS), a family of chemically reactive and unstable oxygen derivatives, are controlled by an intracellular antioxidant system to maintain homeostasis. Higher doses of ROS levels have been associated with the oxidative stress-induced tumor cell death, highlighting the potential of fine-tuning ROS regulation as a target for cancer therapies. The association of ROS mechanism and chordoma remains to be elucidated. In this study, we investigated the effect of targeting the ROS mechanism in chordoma, focusing on superoxide dismutase 1 and superoxide dismutase 2.
Two different chordoma datasets were used to assess oxidative stress-related genes. ROS levels and mitochondrial membrane potential (mtMP) in chordoma cells were measured. The gene expression levels of SOD1 and SOD2 in chordoma patients were also evaluated. SOD2 and SOD1 targeted siRNAs were used to silence gene expression in chordoma cells, and quantitative real-time PCR (qRT-PCR) was used to compare gene expression levels. Apoptotic cell populations were determined using flow cytometry.
The levels of ROS and mtMP were increased in chordoma cell lines compared to healthy nucleus pulposus cells. The chordoma omics data showed induced levels of SOD2. Chordoma tissues also showed high levels of the SOD2 gene. Silencing SOD2 and combined silencing of SOD2 and SOD1 expression increased ROS levels or mtMP, and both induced apoptosis in chordoma cells. ROS imbalance plays a role in chordoma pathogenesis.
SOD2 and SOD1 might be key enzymes in chordoma to modulate ROS levels, and inhibiting the SOD2 and SOD1 activity might be a potential therapeutic target for chordoma treatment.
脊索瘤是一种生长缓慢但具有局部侵袭性和破坏性的骨肿瘤，主要发生在骶骨和斜坡，因其罕见性而带来独特挑战，阻碍了有效治疗策略的发展。全面了解肿瘤生物学对于提出新的治疗方式至关重要。活性氧（ROS）是一类化学反应性强且不稳定的氧衍生物家族，受细胞内抗氧化系统控制以维持体内平衡。较高剂量的ROS水平与氧化应激诱导的肿瘤细胞死亡相关，这凸显了微调ROS调节作为癌症治疗靶点的潜力。ROS机制与脊索瘤的关联仍有待阐明。在本研究中，我们研究了靶向ROS机制对脊索瘤的影响，重点关注超氧化物歧化酶1和超氧化物歧化酶2。
使用两个不同的脊索瘤数据集评估氧化应激相关基因。测量脊索瘤细胞中的ROS水平和线粒体膜电位（mtMP）。还评估了脊索瘤患者中SOD1和SOD2的基因表达水平。使用SOD2和SOD1靶向的小干扰RNA（siRNA）沉默脊索瘤细胞中的基因表达，并使用定量实时聚合酶链反应（qRT-PCR）比较基因表达水平。使用流式细胞术确定凋亡细胞群体。
与健康髓核细胞相比，脊索瘤细胞系中的ROS水平和mtMP升高。脊索瘤组学数据显示SOD2水平升高。脊索瘤组织中SOD2基因水平也较高。沉默SOD2以及联合沉默SOD2和SOD1表达可增加ROS水平或mtMP，两者均诱导脊索瘤细胞凋亡。ROS失衡在脊索瘤发病机制中起作用。
SOD2和SOD1可能是脊索瘤中调节ROS水平的关键酶，抑制SOD2和SOD1活性可能是脊索瘤治疗的潜在靶点。
