Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
Oncol Rep. 2011 Nov;26(5):1259-64. doi: 10.3892/or.2011.1397. Epub 2011 Jul 19.
The development of cervical cancer exhibits some unique differences compared to other solid tumors. Normal cervical stratified epithelia have characteristics of hypoxic tissue. Lack of oxygen (hypoxia) induces the HIF-1 (hypoxia-inducible factor-1) transcription factor, which is a heterodimer composed of a constitutively expressed β subunit and a hypoxia-inducible α-subunit. HIF-1A targets the transcription of over 70 genes involved in many aspects of cancer biology. In well-oxygenated environments, the HIF-1A subunit is hydroxylated, recognized and marked for proteosomal destruction by an E3 ubiquitin ligase, the von Hippel-Lindau protein (pVHL) complex. Under hypoxic stress, proline hydroxylase (PHD) activity is diminished, and stabilized HIF-1A is involved in the activation of the tissue response to hypoxia. Here, we examined the HIF-1A and VHL transcript levels and HIF-1A protein levels in cancerous tissue (n=30) and non-cancerous, normal uterine cervical tissue (n=30). We also compared the methylation status of HIF-1A and of the VHL promoter regions in cancerous and normal tissue samples. Significantly higher levels of HIF-1A and VHL transcripts (p<0.0001 and p=0.0042, respectively) and of HIF-1A protein (p=0.0037) were detected in cancerous tissue compared to normal samples. We did not observe DNA methylation in the HIF-1A and VHL promoter region in either control or cancerous tissue samples. VHL has a functional hypoxia response element (HRE) in the promoter region, and the induction of this HRE acts within a negative feedback loop to limit the hypoxic HIF-1A response. Our findings may suggest that HIF-1A could promote its own degradation by the induction of VHL gene expression (Spearman correlation coefficient, 0.515; p=0.003). Our study shows for the first time that this increase in VHL expression could be HIF-1A-dependent and serves within a negative feedback pathway during hypoxia to regulate the cell-specific oxygen threshold for HIF-1A activation.
宫颈癌的发展与其他实体瘤相比具有一些独特的差异。正常宫颈分层上皮具有缺氧组织的特征。缺氧（Hypoxia）诱导 HIF-1（缺氧诱导因子-1）转录因子，该转录因子由一个组成型表达的β亚基和一个缺氧诱导的α亚基组成。HIF-1A 靶向参与癌症生物学多个方面的 70 多个基因的转录。在富氧环境中，HIF-1A 亚基被羟化，被 von Hippel-Lindau 蛋白（pVHL）复合物的 E3 泛素连接酶识别和标记为蛋白酶体破坏。在缺氧应激下，脯氨酰羟化酶（PHD）活性降低，稳定的 HIF-1A 参与组织对缺氧的反应激活。在这里，我们检查了癌症组织（n=30）和非癌性、正常子宫颈组织（n=30）中 HIF-1A 和 VHL 的转录本水平和 HIF-1A 蛋白水平。我们还比较了癌症和正常组织样本中 HIF-1A 和 VHL 启动子区域的甲基化状态。与正常样本相比，癌症组织中 HIF-1A 和 VHL 转录本（p<0.0001 和 p=0.0042，分别）和 HIF-1A 蛋白（p=0.0037）水平显著升高。我们没有观察到控制或癌症组织样本中 HIF-1A 和 VHL 启动子区域的 DNA 甲基化。VHL 在启动子区域具有功能缺氧反应元件（HRE），并且该 HRE 的诱导在负反馈环内起作用，以限制缺氧 HIF-1A 反应。我们的发现可能表明 HIF-1A 可以通过诱导 VHL 基因表达来促进自身降解（Spearman 相关系数，0.515；p=0.003）。我们的研究首次表明，这种 VHL 表达的增加可能是 HIF-1A 依赖性的，并在缺氧期间作为负反馈途径内起作用，以调节 HIF-1A 激活的细胞特异性氧阈值。
