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首页> 外文期刊>Cancer biology & therapy >Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver
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Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver

机译：非肝肿瘤改变了肝脏中编码铜转运蛋白的基因的活性

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To assess the statistical relationship between tumor growth and copper metabolism, we performed a meta-analysis 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 meta-analysis shows that in the majority of cases (more than 3,100 patients), tumor growth positively correlates with the copper status indexes. Nude athymic CD-1 nuu mice with subcutaneous tumors of human origin, C57Bl/6J mice with murine melanoma and ApcMin 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 c increased significantly in the cytosol, while decreasing in the mitochondria. We discuss a possible trans-effect of developing tumors on copper metabolism in the liver.
机译：为了评估肿瘤生长与铜代谢之间的统计关系，我们进行了一项研究的荟萃分析，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）对肿瘤患者进行了表征。我们的荟萃分析显示，在大多数情况下（超过3,100例患者），肿瘤的生长与铜状态指数呈正相关。研究了人类源性皮下肿瘤的裸性无胸腺CD-1 nu / nu小鼠，鼠黑色素瘤的C57Bl / 6J小鼠和整个肠道自发形成腺瘤的ApcMin小鼠，以实验确定肿瘤进展，肝铜代谢和铜状态指标。我们表明，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与铜蓝蛋白金属化相关的基因（CTR1和ATP7B）的表达显着增加。此外，还检测到存在编码由肝细胞非典型的糖基磷脂酰肌醇锚定至质膜的铜蓝蛋白形式的mRNA剪接变体。 ATP7A铜转运蛋白基因（通常仅在胚胎铜代谢期间才在肝脏中表达）也被激活。整体铜蓝蛋白的消耗导致人HCT116结肠癌细胞在裸鼠中生长受阻，并在肿瘤细胞中引起DNA断裂。此外，细胞色素c的浓度在细胞质中显着增加，而在线粒体中则降低。我们讨论了发展中的肿瘤对肝脏铜代谢的可能的反式作用。

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