Renal cancer cells lacking hypoxia inducible factor (HIF)-1α expression maintain vascular endothelial growth factor expression through HIF-2α
Renal cancer cells lacking hypoxia inducible factor (HIF)-1α expression maintain vascular endothelial growth factor expression through HIF-2α
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DOI：
10.1093/carcin/bgl143
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发表时间：
2007-03-01
期刊：
影响因子：
4.7
通讯作者：
Murai, Masaru
中科院分区：
文献类型：
--
作者：
Shinojima, Toshiaki;Oya, Mototsugu;Murai, Masaru
最近的努力旨在靶向低氧诱导因子（HIF）介导的低氧诱导基因通路用于肾细胞癌（RCC）治疗。在HIF诱导的多种基因中，血管内皮生长因子（VEGF）是血管生成、肿瘤生长和转移的关键介质之一。然而，到目前为止，有限的信息是可利用的功能差异VEGF转录之间的HIF亚基，即HIF-1 α和HIF-2 α。为了研究HIF-1 α和HIF-2 α对RCC中VEGF基因诱导的依赖性作用，分析了一组人RCC细胞系。我们发现HIF-1 α蛋白表达的缺失是RCC细胞系中的常见事件，这不仅与截短的HIF-1 α mRNA转录物有关，而且与转录沉默有关。由于在RCC细胞系中，HIF-1 α基因的富含CpG的启动子区含有类似频率的甲基化CpG二核苷酸，因此这种现象可能涉及复杂且不均匀的机制。在这些HIF-1 α缺陷细胞系中，HIF-2 α基因的敲低表明HIF-2 α调节VEGF的产生，而与VHL基因突变状态无关。相反，在表达野生型HIF-1 α和HIF-2 α蛋白的细胞中，HIF-1 α在VEGF分泌中起主要作用。因此，HIF-1 α可能是RCC治疗的重要靶分子;然而，HIF-2 α应该靶向HIF-1 α缺陷的肾癌细胞。
Recent efforts have been aimed at targeting the hypoxia inducible factor (HIF)-mediated hypoxia-induced gene pathway for renal cell carcinomas (RCC) therapy. Among the various genes induced by HIF, vascular endothelial growth factor (VEGF) is one of the critical mediators in angiogenesis, tumor growth and metastasis. To date, however, limited information is available on the functional differences regarding VEGF transcription between the HIF subunits, namely HIF-1 alpha and HIF-2 alpha. To investigate the HIF-1 alpha and HIF-2 alpha-dependent effect on VEGF gene induction in RCC, a panel of human RCC cell lines was analyzed. We found that a loss of HIF-1 alpha protein expression was a common event in RCC cell lines, which was associated not only with truncated HIF-1 alpha mRNA transcripts but also with transcriptional silencing. Since the CpG rich promoter region of the HIF-1 alpha gene contained a similar frequency of methylated CpG dinucleotides in RCC cell lines, a complex and non-uniform mechanism may be involved in this phenomenon. In these HIF-1 alpha defective cell lines, the knockdown of the HIF-2 alpha gene demonstrated that HIF-2 alpha regulated the VEGF production, irrespective of the VHL gene mutation status. In contrast, HIF-1 alpha played a predominant role in VEGF secretion in the cells expressing both wild-type HIF-1 alpha and HIF-2 alpha proteins. HIF-1 alpha may therefore represent an important target molecule for RCC therapy; however, HIF-2 alpha should be targeted in HIF-1 alpha defective renal cancer cells.