癌细胞不断进化以适应环境变化，特别是在接受药物治疗期间。在这项工作中，我们旨在表征线粒体 DNA (mtDNA) 的遗传和表观遗传变化，这些变化可能会增加口腔鳞状细胞癌 (OSCC) 对顺铂的耐药性。我们首先通过持续约 4 个月的顺铂治疗，从两种人类 OSCC 细胞系（即 SAS 和 H103）中获得耐药细胞。为了确定顺铂诱导的 mtDNA 变化，我们对处理前后从细胞中提取的 mtDNA 进行了纳米孔测序和定量聚合酶链反应分析。我们还评估了细胞的线粒体功能及其产生细胞内活性氧（ROS）的能力。我们发现，在源自 SAS 的顺铂耐药细胞中，mtDNA 含量减少，MT-ND1 基因中 m.3910G > C 突变显着富集。然而，在顺铂耐药的H103细胞中没有检测到这种变化。顺铂治疗还改变了 SAS 和 H103 细胞的甲基化模式，并降低了它们对 ROS 诱导的细胞毒性的敏感性。我们认为 mtDNA 的序列改变和表观遗传变化以及 mtDNA 含量的减少可能是 OSCC 顺铂耐药的关键驱动因素。这些 mtDNA 改变可能参与细胞适应，作为对环境不利变化的反应，特别是暴露于细胞毒性剂。重要的是，观察到的 mtDNA 变化可能受到各种癌症亚型的独特遗传景观的影响。总体而言，这项研究揭示了复杂 mtDNA 动态驱动的顺铂耐药性的重要见解，特别是在 OSCC 中。这强调需要根据个体 OSCC 患者的基因图谱定制靶向治疗，以改善疾病预后。© 2024。作者。

Cancer cells are constantly evolving to adapt to environmental changes, particularly during exposure to drug treatment. In this work, we aimed to characterize genetic and epigenetic changes in mitochondrial DNA (mtDNA) that may increase the resistance of oral squamous cell carcinoma (OSCC) to cisplatin. We first derived drug-resistant cells from two human OSCC cell lines, namely SAS and H103, by continual cisplatin treatments for about 4 months. To determine mtDNA changes induced by cisplatin, we performed nanopore sequencing and quantitative polymerase chain reaction analysis of mtDNA extracted from the cells pre- and post-treatment. We also assessed the mitochondrial functions of the cells and their capacity to generate intracellular reactive oxygen species (ROS). We found that in the cisplatin-resistant cells derived from SAS, there was a reduction in mtDNA content and significant enrichment of a m.3910G > C mutation in the MT-ND1 gene. However, such changes were not detected in cisplatin-resistant H103 cells. The cisplatin treatment also altered methylation patterns in both SAS and H103 cells and decreased their sensitivity to ROS-induced cytotoxicity. We suggest that the sequence alterations and epigenetic changes in mtDNA and the reduction in mtDNA content could be key drivers of cisplatin resistance in OSCC. These mtDNA alterations may participate in cellular adaptation that serves as a response to adverse changes in the environment, particularly exposure to cytotoxic agents. Importantly, the observed mtDNA changes may be influenced by the distinct genetic landscapes of various cancer subtypes. Overall, this study reveals significant insights into cisplatin resistance driven by complex mtDNA dynamics, particularly in OSCC. This underscores the need for targeted therapies tailored to the genetic profiles of individual OSCC patients to improve disease prognosis.© 2024. The Author(s).