University Medical Center Regensburg, D-93053 Regensburg, Germany.
Eur J Cancer. 2010 Apr;46(6):1159-69. doi: 10.1016/j.ejca.2010.01.031. Epub 2010 Feb 23.
The hypoxia-inducible factor-1 (HIF-1), which consists of the constitutive HIF-1beta and the oxygen-responsive HIF-1alpha subunit, is the master activator of the cellular transcriptional response to hypoxia coordinating gene expression during reduced oxygen tension. Overexpression of HIF-1 and increased transcriptional activity induced by hypoxia are linked to progression of many tumour types such as head and neck cancer, cervical carcinoma, leukaemia and renal cell carcinoma. In this study, we demonstrate that HIF activity is increased in malignant melanoma cells already under normoxic conditions in contrast to other tumour types. HIF-1alpha and -2alpha knockdown by siRNA transfection revealed that this effect is due to constitutive HIF-1alpha expression. Furthermore, the inhibition or activation of reactive oxygen species (ROS) decreased or activated, respectively, HIF-1 activity and HIF-1alpha protein expression. Interestingly, the inhibition of the NFkappaB pathway also reduced the accumulation of HIF-1alpha assuming a context between ROS and NFkappaB, and suggesting that ROS and NFkappaB activity contribute to HIF-1alpha accumulation. In summary, we identified an increased HIF-1alpha protein expression and activity in melanoma under normoxia mediated by ROS and the NFkappaB pathway.
缺氧诱导因子-1（HIF-1）由组成型 HIF-1β和氧反应性 HIF-1α亚基组成，是细胞对缺氧反应的主要转录激活剂，协调低氧张力下的基因表达。HIF-1 的过表达和缺氧诱导的转录活性增加与许多肿瘤类型的进展有关，如头颈部癌症、宫颈癌、白血病和肾细胞癌。在这项研究中，我们证明与其他肿瘤类型相比，恶性黑色素瘤细胞在常氧条件下 HIF 活性增加。通过 siRNA 转染敲低 HIF-1α 和 -2α，表明这种效应是由于组成型 HIF-1α 表达。此外，活性氧（ROS）的抑制或激活分别降低或激活了 HIF-1 活性和 HIF-1α 蛋白表达。有趣的是，NFκB 通路的抑制也减少了 HIF-1α 的积累，假设 ROS 和 NFκB 之间存在关联，并表明 ROS 和 NFκB 活性有助于 HIF-1α 的积累。总之，我们确定了常氧下黑色素瘤中 HIF-1α 蛋白表达和活性的增加，这是由 ROS 和 NFκB 通路介导的。
