The hypoxia-inducible factor-1α is a negative factor for tumor therapy
The hypoxia-inducible factor-1α is a negative factor for tumor therapy
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DOI：
10.1038/sj.onc.1206385
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发表时间：
2003-05-22
期刊：
影响因子：
8
通讯作者：
Wenger, RH
中科院分区：
文献类型：
--
作者：
Unruh, A;Ressel, A;Wenger, RH
肿瘤缺氧通过增加编码血管生成、代谢和转移因子的基因的表达来负调节细胞生长并导致更恶性的表型。具有临床重要性的是，肿瘤氧合不足通过知之甚少的机制影响化疗和放疗的效率。缺氧诱导因子（HIF）-1是氧调节基因的主要转录激活因子，并且HIF-1在几种肿瘤类型中组成性上调。因此，HIF-1可能与肿瘤治疗耐药性有关。我们发现，转化的小鼠胚胎成纤维细胞缺乏HIF-1 α更容易受到治疗与卡铂，依托泊苷和电离辐射比野生型细胞。HIF-1 α缺陷细胞中细胞死亡增加是由于细胞凋亡，不涉及p53诱导。在免疫功能低下的小鼠中，用卡铂和依托泊苷对实验性纤维肉瘤进行肿瘤化疗证实了HIF 1 α缺陷细胞的敏感性增强。不引起DNA双链断裂的药物，如DNA合成抑制剂或DNA单链断裂引起的药物同样损害细胞生长，与HIF-1 α基因型无关。在HIF-1a缺陷细胞中，片段化报告基因的功能修复减少。因此，缺氧非依赖性的基础HIF-1 α在肿瘤细胞中的表达，如已知的从未转化的胚胎干细胞，足以诱导靶基因的表达，可能包括DNA双链断裂修复酶。
Tumor hypoxia negatively regulates cell growth and causes a more malignant phenotype by increasing the expression of genes encoding angiogenic, metabolic and metastatic factors. Of clinical importance, insufficient tumor oxygenation affects the efficiency of chemotherapy and radiotherapy by poorly understood mechanisms. The hypoxia-inducible factor (HIF)-1 is a master transcriptional activator of oxygen-regulated genes and HIF-1 is constitutively upregulated in several tumor types. HIF-1 might thus be implicated in tumor therapy resistance. We found that transformed mouse embryonic fibroblasts deficient for HIF-1alpha are more susceptible to the treatment with carboplatin, etoposide and ionizing radiation than wild-type cells. Increased cell death in HIF-1alpha-deficient cells was because of apoptosis and did not involve p53 induction. Tumor chemotherapy of experimental fibrosarcoma in immunocompromised mice with carboplatin and etoposide confirmed the enhanced susceptibility of HIF1alpha-deficient cells. Agents that did not cause DNA double-strand breaks, such as DNA-synthesis inhibitors or a DNA single-strand break-causing agent equally impaired cell growth, independent of the HIF-1alpha genotype. Functional repair of a fragmented reporter gene was decreased in HIF-la-deficient cells. Thus, hypoxia-independent basal HIF-1alpha expression in tumor cells, as known from untransformed embryonic stem cells, is sufficient to induce target gene expression, probably including DNA double strand break repair enzymes.