Arsenic trioxide (As₂O₃) is a promising effective chemotherapeutic agent for cancer treatment; however, how and through what molecular mechanisms the oxidative damage of As₂O₃ is controlled remains poorly understood. Recently, the involvement of dysregulated long noncoding RNA ovarian tumor domain containing 6B antisense RNA1 (lncRNA OTUD6B-AS1) in tumorigenesis is established. Here, for the first time, we characterize the regulation of As₂O₃ in the oxidative damage against bladder cancer via lncRNA OTUD6B-AS1. As₂O₃ could activate lncRNA OTUD6B-AS1 transcription in bladder cancer cells, and these findings were validated in a xenograft tumor model. Functional assays showed that lncRNA OTUD6B-AS1 dramatically exacerbated As₂O₃-mediated oxidative damage by inducing oxidative stress. Mechanistically, As₂O₃ increased levels of metal-regulatory transcription factor 1 (MTF1), which regulates lncRNA OTUD6B-AS1, in response to oxidative stress. Further, lncRNA OTUD6B-AS1 inhibited mitochondrial NADP⁺-dependent isocitrate dehydrogenase 2 (IDH2) expression by stabilizing miR-6734-5p, which contributed to cytotoxicity by enhancing oxidative stress. Together, our findings offer new insights into the mechanism of As₂O₃-induced oxidative damage and identify important factors in the pathway, As₂O₃/lncRNA OTUD6B-AS1/miR-6734-5p/IDH2, expanding the knowledge of activity of As₂O₃ as cancer treatment.

中文翻译：

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lncRNA OTUD6B-AS1 通过 miR-6734-5p 介导的 IDH2 功能抑制加剧 As2O3 诱导的膀胱癌氧化损伤。

三氧化二砷（As ₂ O ₃）是一种很有前途的癌症治疗有效化疗剂；_{然而，如何以及通过何种分子机制控制 As 2} O ₃的氧化损伤仍然知之甚少。最近，已确定含有 6B 反义 RNA1 (lncRNA OTUD6B-AS1) 的长链非编码 RNA 卵巢肿瘤结构域参与肿瘤发生。在这里，我们首次通过 lncRNA OTUD6B-AS1表征 As ₂ O _{3在对膀胱癌的氧化损伤中的调节。}作为₂ O ₃可以激活膀胱癌细胞中的 lncRNA OTUD6B-AS1 转录，这些发现在异种移植肿瘤模型中得到了验证。功能分析表明，lncRNA OTUD6B-AS1通过诱导氧化应激显着加剧了 As ₂ O _{3介导的氧化损伤。}从机制上讲，As ₂ O ₃增加了金属调节转录因子 1 (MTF1) 的水平，该转录因子调节 lncRNA OTUD6B-AS1，以响应氧化应激。此外，lncRNA OTUD6B-AS1 通过稳定 miR-6734-5p 抑制线粒体 NADP ⁺依赖性异柠檬酸脱氢酶 2 (IDH2) 的表达，这通过增强氧化应激导致细胞毒性。_{总之，我们的研究结果为 As 2}的机制提供了新的见解O ₃诱导的氧化损伤和识别通路中的重要因素，As ₂ O ₃ /lncRNA OTUD6B-AS1/miR-6734-5p/IDH2，扩展了 As ₂ O ₃作为癌症治疗活性的知识。