Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver
Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver
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DOI：
10.4161/cbt.24594
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发表时间：
2013-07-01
影响因子：
3.6
通讯作者：
Broggini, Massimo
中科院分区：
文献类型：
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作者：
Babich, Polina S.;Skvortsov, Alexey N.;Broggini, Massimo
为了评估肿瘤生长与铜代谢之间的统计关系，我们对研究进行了荟萃分析，其中根据任何铜状态指标（原子铜血清浓度、血清氧化酶活性、铜蓝蛋白含量）对肿瘤患者进行表征。我们的荟萃分析表明，在大多数病例（超过 3100 名患者）中，肿瘤生长与铜状态指数呈正相关。研究人员对患有人源皮下肿瘤的裸无胸腺 CD-1 nu/nu 小鼠、患有鼠黑色素瘤的 C57Bl/6J 小鼠和患有整个肠道自发性腺瘤的 Apc(Min) 小鼠进行了研究，以通过实验确定肿瘤进展、肝铜代谢和铜状态指标之间的关系。我们发现铜状态指数在肿瘤生长过程中显着增加。在荷瘤小鼠的肝组织中，铜蓝蛋白基因表达以及铜蓝蛋白金属化相关基因（CTR1和ATP7B）的表达显着增加。此外，还检测到存在编码通过糖基磷脂酰肌醇锚定在质膜上的铜蓝蛋白形式的mRNA剪接变体，这对于肝细胞来说是非典型的。通常仅在胚胎铜代谢期间在肝脏中表达的 ATP7A 铜转运蛋白基因也被激活。全铜蓝蛋白的消耗会导致裸鼠体内人 HCT116 结肠癌细胞生长迟缓，并诱导肿瘤细胞中的 DNA 断裂。此外，细胞质中细胞色素的浓度显着增加，而线粒体中细胞色素的浓度则降低。我们讨论了肿瘤发展对肝脏铜代谢可能产生的反式效应。
To assess the statistical relationship between tumor growth and copper metabolism, we performed a metaanalysis of studies in which patients with neoplasms were characterized according to any of the copper status indexes (atomic copper serum concentration, serum oxidase activity, ceruloplasmin protein content). Our metaanalysis shows that in the majority of cases (more than 3100 patients), tumor growth positively correlates with the copper status indexes. Nude athymic CD-1 nu/nu mice with subcutaneous tumors of human origin, C57Bl/6J mice with murine melanoma and Apc(Min) mice with spontaneously developing adenomas throughout the intestinal tract were studied to experimentally determine the relationship between tumor progression, liver copper metabolism, and copper status indexes. We showed that the copper status indexes increased significantly during tumor growth. In the liver tissue of tumor-bearing mice, ceruloplasmin gene expression, as well as the expression of genes related to ceruloplasmin metallation (CTR1 and ATP7B), increased significantly. Moreover, the presence of an mRNA splice variant encoding a form of ceruloplasmin anchored to the plasma membrane by glycosylphosphatidyl inositol, which is atypical for hepatocytes, was also detected. The ATP7A copper transporter gene, which is normally expressed in the liver only during embryonic copper metabolism, was also activated. Depletion of holo-ceruloplasmin resulted in retardation of human HCT116 colon carcinoma cell growth in nude mice and induced DNA fragmentation in tumor cells. In addition, the concentration of cytochrome cincreased significantly in the cytosol, while decreasing in the mitochondria. We discuss a possible trans-effect of developing tumors on copper metabolism in the liver.