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

lncRNA OTUD6B-AS1 Exacerbates AsO-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2.

机构信息

Department of Environmental Health, China Medical University, Shenyang 110122, China.

Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China.

出版信息

Oxid Med Cell Longev. 2020 Sep 1;2020:3035624. doi: 10.1155/2020/3035624. eCollection 2020.

DOI:10.1155/2020/3035624
PMID:32952848
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7481943/
Abstract

Arsenic trioxide (AsO) is a promising effective chemotherapeutic agent for cancer treatment; however, how and through what molecular mechanisms the oxidative damage of AsO 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 AsO in the oxidative damage against bladder cancer via lncRNA OTUD6B-AS1. AsO 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 AsO-mediated oxidative damage by inducing oxidative stress. Mechanistically, AsO 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 AsO-induced oxidative damage and identify important factors in the pathway, AsO/lncRNA OTUD6B-AS1/miR-6734-5p/IDH2, expanding the knowledge of activity of AsO as cancer treatment.

摘要

三氧化二砷 (AsO) 是一种有前途的癌症治疗有效化疗药物；然而，AsO 的氧化损伤是如何以及通过什么分子机制来控制的，目前仍知之甚少。最近，失调的长非编码 RNA 卵巢肿瘤结构域包含 6B 反义 RNA1（lncRNA OTUD6B-AS1）在肿瘤发生中的作用已得到证实。在这里，我们首次描述了通过 lncRNA OTUD6B-AS1 来调节 AsO 在膀胱癌氧化损伤中的作用。AsO 可在膀胱癌细胞中激活 lncRNA OTUD6B-AS1 的转录，这一发现已在异种移植肿瘤模型中得到验证。功能测定表明，lncRNA OTUD6B-AS1 通过诱导氧化应激，极大地加剧了 AsO 介导的氧化损伤。从机制上讲，AsO 增加了金属调节转录因子 1（MTF1）的水平，该因子调节 lncRNA OTUD6B-AS1，以应对氧化应激。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，通过增强氧化应激促进细胞毒性。总之，我们的研究结果为 AsO 诱导的氧化损伤机制提供了新的见解，并确定了该途径中的重要因素，AsO/lncRNA OTUD6B-AS1/miR-6734-5p/IDH2，扩展了 AsO 作为癌症治疗活性的知识。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/c4104cadb3cc/OMCL2020-3035624.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/328e629d88cc/OMCL2020-3035624.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/53c0d8a81511/OMCL2020-3035624.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/4168d9faf9e9/OMCL2020-3035624.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/217983a86bbe/OMCL2020-3035624.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/2532936af160/OMCL2020-3035624.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/a02840fef672/OMCL2020-3035624.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/c4104cadb3cc/OMCL2020-3035624.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/328e629d88cc/OMCL2020-3035624.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/53c0d8a81511/OMCL2020-3035624.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/4168d9faf9e9/OMCL2020-3035624.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/217983a86bbe/OMCL2020-3035624.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/2532936af160/OMCL2020-3035624.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/a02840fef672/OMCL2020-3035624.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0043/7481943/c4104cadb3cc/OMCL2020-3035624.007.jpg

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