Department of Pediatrics, Dana Children's Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel.
Cell Cycle. 2010 Sep 15;9(18):3723-9. Epub 2010 Sep 7.
Parathyroid hormone-related protein (PTHrP) expressed by human cancer cells enhances tumor cell growth and metastasis in vivo and it is considered as the major factor responsible for humoral hypercalcemia of malignancy. Hypoxia is a widespread feature of most solid tumors. Here, we studied the effects of hypoxia on PTHrP expression. We found that PTHrP is transcriptionally induced by prolonged (48 h) hypoxia in multiple human cancer and endothelial cell lines. Pharmacological up or downregulation of hypoxia-inducible factor (HIF) resulted in induction or reduction of PTHrP levels, respectively, implying that PTHrP hypoxic induction is mediated by HIF pathway. Analysis of PTHrP promoter revealed that both HIF-1α and HIF-2α subunits bind to specific hypoxia-responsive elements (HRE) within the P2 promoter of PTHrP. However, only HIF-2α can drive direct transcriptional activation, which can be abolished by mutation in the specific HRE. To the best of our knowledge, these results provide for the first time evidence that PTHrP is regulated by hypoxia in cancer and endothelial cells through the HIF-2 pathway. We suggest that HIF-2 induced by intratumoral hypoxia or by other genetic alterations may contribute to the pathogenesis of hypercalcemia of malignancy and cancer aggressiveness by stimulation of PTHrP expression.
人癌细胞表达的甲状旁腺激素相关蛋白（PTHrP）增强了体内肿瘤细胞的生长和转移，被认为是导致恶性肿瘤体液性高钙血症的主要因素。缺氧是大多数实体瘤的普遍特征。在这里，我们研究了缺氧对 PTHrP 表达的影响。我们发现，在多种人癌细胞和内皮细胞系中，长时间（48 小时）缺氧可转录诱导 PTHrP。缺氧诱导因子（HIF）的药理学上调或下调分别导致 PTHrP 水平的诱导或降低，这表明 PTHrP 的缺氧诱导是由 HIF 途径介导的。对 PTHrP 启动子的分析表明，HIF-1α 和 HIF-2α 亚基都结合到 PTHrP P2 启动子内的特定缺氧反应元件（HRE）上。然而，只有 HIF-2α 可以驱动直接转录激活，而在特定 HRE 中的突变可以使其失活。据我们所知，这些结果首次提供了证据，表明在癌症和内皮细胞中，PTHrP 通过 HIF-2 途径受到缺氧的调节。我们认为，肿瘤内缺氧或其他遗传改变诱导的 HIF-2 可能通过刺激 PTHrP 表达，导致恶性肿瘤高钙血症和癌症侵袭性的发病机制。
