Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer.
Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer.
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DOI：
10.1371/journal.pone.0043403
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Toyokuni S
中科院分区：
文献类型：
--
作者：
Akatsuka S;Yamashita Y;Ohara H;Liu YT;Izumiya M;Abe K;Ochiai M;Jiang L;Nagai H;Okazaki Y;Murakami H;Sekido Y;Arai E;Kanai Y;Hino O;Takahashi T;Nakagama H;Toyokuni S
铁超载与人类的癌症发生有关。在啮齿动物的肾脏近端小管内注射氮三醋酸铁可引起Fenton反应，在反复治疗后最终导致高发病率的肾细胞癌(RCC)。我们进行了高分辨率微阵列比较基因组杂交，以确定氧化应激诱导的大鼠肾小管上皮细胞基因组图谱中的特征。结果显示了广泛的大规模基因组改变，并倾向于缺失。大量的缺失和扩增，有时甚至是片段性的，表明芬顿反应是体内这种基因组变化的原因。频率图显示，两个最常见的改变基因座对应于CDKN2a/2b缺失和Met扩增。肿瘤大小与Met表达和/或扩增成比例相关，聚类分析证实了我们的结果。此外，我们开发了一种基于染色体同线关系的程序来比较不同物种之间拷贝数变化的整个基因组模式。在五种人类癌症中，大鼠RCC的模式显示出与人类RCC的最相似之处，其次是人类恶性间皮瘤，一种与铁负荷过高相关的癌症。因此，铁依赖的Fenton化学反应在癌变过程中会引起大规模的基因组改变，这可能导致不同的基因组图谱。基于人类癌症中广泛的基因组改变的特点，我们的结果表明，这种化学反应可能在人类癌症的发生过程中发挥重要作用。
Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.
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