Low Ascorbate Levels Are Associated with Increased Hypoxia-Inducible Factor-1 Activity and an Aggressive Tumor Phenotype in Endometrial Cancer
Low Ascorbate Levels Are Associated with Increased Hypoxia-Inducible Factor-1 Activity and an Aggressive Tumor Phenotype in Endometrial Cancer
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DOI：
10.1158/0008-5472.can-10-0263
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Vissers, Margreet C. M.
中科院分区：
文献类型：
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作者：
Kuiper, Caroline;Molenaar, Ilona G. M.;Vissers, Margreet C. M.
转录因子缺氧诱导因子(HIF)-1的激活允许实体肿瘤在代谢应激条件下茁壮成长。因为HIF-1被需要抗坏血酸的羟基化反应关闭，细胞内抗坏血酸水平不足可能导致HIF-1过度激活。在这项研究中，我们研究了人子宫内膜肿瘤（已知由HIF-1和血管内皮生长因子（VEGF）驱动）的抗坏血酸含量是否影响HIF-1活性和肿瘤病理。我们测量了肿瘤和患者匹配的正常子宫内膜组织样本中HIF-1 α和三个下游基因产物[葡萄糖转运蛋白1 (GLUT-1)， Bcl-2/腺病毒E1B 19kda相互作用蛋白3 （BNIP3）和VEGF]的蛋白水平，以及抗坏血酸含量。HIF-1 α及其下游基因产物在肿瘤组织中表达上调，在高级别肿瘤中表达水平最高。与正常组织相比，高级别肿瘤积累抗坏血酸的能力也降低；然而，所有级别的肿瘤都含有低抗坏血酸含量。HIF-1 α蛋白含量最高的肿瘤是抗坏血酸缺乏的。低抗坏血酸水平还与VEGF、GLUT-1和BNIP3蛋白水平升高以及肿瘤大小增加有关，低组织抗坏血酸水平与HIF-1通路激活增加之间存在显著关联（P = 0.007）。相反，具有高抗坏血酸水平的肿瘤具有较低水平的HIF-1激活。这项研究首次显示了抗坏血酸和HIF-1之间可能的体内关系，低肿瘤组织抗坏血酸水平与高HIF-1激活和肿瘤生长有关。癌症Res;70 (14);5749 - 58。AACR (C) 2010。
Activation of the transcription factor hypoxia-inducible factor (HIF)-1 allows solid tumors to thrive under conditions of metabolic stress. Because HIF-1 is switched off by hydroxylation reactions that require ascorbate, inadequate intracellular ascorbate levels could contribute to HIF-1 overactivation. In this study, we investigated whether the ascorbate content of human endometrial tumors [known to be driven by HIF-1 and vascular endothelial growth factor (VEGF)] influenced HIF-1 activity and tumor pathology. We measured protein levels of HIF-1 alpha and three downstream gene products [glucose transporter 1 (GLUT-1), Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and VEGF], as well as the ascorbate content of tumor and patient-matched normal endometrial tissue samples. HIF-1 alpha and its downstream gene products were upregulated in tumor tissue, with the highest levels being present in high-grade tumors. High-grade tumors also had reduced capacity to accumulate ascorbate compared with normal tissue; however, all grades contained tumors with low ascorbate content. Tumors with the highest HIF-1 alpha protein content were ascorbate deficient. Low ascorbate levels were also associated with elevated VEGF, GLUT-1, and BNIP3 protein levels and with increased tumor size, and there was a significant association between low tissue ascorbate levels and increased activation of the HIF-1 pathway (P = 0.007). In contrast, tumors with high ascorbate levels had lesser levels of HIF-1 activation. This study shows for the first time a likely in vivo relationship between ascorbate and HIF-1, with low tumor tissue ascorbate levels being associated with high HIF-1 activation and tumor growth. Cancer Res; 70(14); 5749-58. (C)2010 AACR.