ROS control in human iPS cells reveals early events in spontaneous carcinogenesis
ROS control in human iPS cells reveals early events in spontaneous carcinogenesis
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DOI：
10.1093/carcin/bgz081
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发表时间：
2020-01-01
期刊：
影响因子：
4.7
通讯作者：
Sekiguchi, Mutsuo
中科院分区：
文献类型：
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作者：
Oka, Sugako;Hayashi, Michio;Sekiguchi, Mutsuo
在细胞呼吸过程中产生的活性氧（ROS）氧化各种细胞成分，导致致癌。由于大多数关于ROS在癌变中的作用的研究主要是在肿瘤来源的细胞系中进行的，这些细胞系含有各种类型的突变，因此很难确定导致癌症形成的分子细节。为了克服这一困难，我们建立了人类诱导的多能干细胞系，通过操纵产生ROS的线粒体来控制细胞内ROS水平在不同分化阶段。通过在线粒体呼吸链复合体II的组成部分琥珀酸脱氢酶复合体（亚基C蛋白）中引入特定的氨基酸取代（169E）， ROS水平显著提高。将内胚层分化早期ros过量生成细胞皮下接种于裸鼠背部，观察肿瘤形成。通过RNA测序对这些肿瘤起始细胞进行全面分析。结果显示，与对照细胞相比，肿瘤启动细胞有27个转录本上调。新发现的基因包括编码PAX8和FOSB（转录因子）以及FGF22的基因，这些基因的表达在发育中的胚胎中会增加。这些结果表明，这些基因可能在细胞分化的早期阶段在癌症的形成中起关键作用。
Reactive oxygen species (ROS) generated during cellular respiration oxidize various cellular constituents, which cause carcinogenesis. Because most studies on the role of ROS in carcinogenesis have mainly been performed using tumorderived cell lines, which harbor various types of mutation, it has been difficult to determine the molecular details that lead to cancer formation. To overcome this difficulty, we established human-induced pluripotent stem cell lines in which the intracellular ROS levels are controlled at various differentiation stages by manipulating the ROS-yielding mitochondria. By introducing a specific amino acid substitution (169E) into the succinate dehydrogenase complex, subunit C protein, a component of mitochondrial respiratory chain complex II, the ROS level increased considerably. When ROS-overproducing cells at the early stage of endoderm differentiation were subcutaneously inoculated into the backs of nude mice, we observed tumor formation. These tumor-initiating cells were subjected to a comprehensive analysis by RNA sequencing. It was revealed that tumor-initiating cells showed 27 upregulated transcripts compared with control cells. The newly identified genes include those coding for PAX8 and FOSB (transcription factors) as well as FGF22, whose expressions are known to increase in developing embryos. These results suggest that these genes may play a pivotal role in cancer formation at the very early stages of cell differentiation.