Constitutive HIF-1 activity in malignant melanoma
Constitutive HIF-1 activity in malignant melanoma
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DOI：
10.1016/j.ejca.2010.01.031
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发表时间：
2010-04-01
影响因子：
8.4
通讯作者：
Bosserhoff, Anja-Katrin
中科院分区：
文献类型：
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作者：
Kuphal, Silke;Winklmeier, Andreas;Bosserhoff, Anja-Katrin
低氧诱导因子-1（HIF-1）由组成型HIF-1 β和氧响应性HIF-1 α亚基组成，是氧张力降低时细胞对低氧的转录反应的主要激活因子，低氧诱导HIF-1的过表达和转录活性增加与许多肿瘤类型如头颈癌、乳腺癌宫颈癌、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，在含氧量正常的条件下，恶性黑色素瘤细胞中HIF活性增加。通过siRNA转染的HIF-1 α和HIF-2 α敲低揭示了这种效应是由于组成型HIF-1 α表达。此外，活性氧（ROS）的抑制或激活分别降低或激活HIF-1活性和HIF-1 α蛋白表达。有趣的是，NF κ B途径的抑制也减少了HIF-1 α的积累，假设ROS和NF κ B之间的背景，并表明ROS和NF κ B活性有助于HIF-1 α的积累。总之，我们确定了在正常氧下由ROS和NF κ B通路介导的黑色素瘤中HIF-1 α蛋白表达和活性增加。(C)2010爱思唯尔有限公司版权所有。
The hypoxia-inducible factor-1 (HIF-1), which consists of the constitutive HIF-1 beta and the oxygen-responsive HIF-1 alpha 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-1 alpha and -2 alpha knockdown by siRNA transfection revealed that this effect is due to constitutive HIF-1 alpha expression. Furthermore, the inhibition or activation of reactive oxygen species (ROS) decreased or activated, respectively, HIF-1 activity and HIF-1 alpha protein expression. Interestingly, the inhibition of the NFkappaB pathway also reduced the accumulation of HIF-1 alpha assuming a context between ROS and NFkappaB, and suggesting that ROS and NFkappaB activity contribute to HIF-1 alpha accumulation. In summary, we identified an increased HIF-1 alpha protein expression and activity in melanoma under normoxia mediated by ROS and the NFkappaB pathway. (C) 2010 Elsevier Ltd. All rights reserved.