Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia: involvement of Nrf2.
Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia: involvement of Nrf2.
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DOI：
10.1007/s00109-016-1439-7
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发表时间：
2016-10
影响因子：
4.7
通讯作者：
Kietzmann, Thomas
中科院分区：
文献类型：
--
作者：
al Taleb, Zukaa;Petry, Andreas;Chi, Tabughang Franklin;Mennerich, Daniela;Goerlach, Agnes;Dimova, Elitsa Y.;Kietzmann, Thomas
关键词：
亚砷酸盐（As（III））广泛分布于自然界中，可在水、食物和空气中发现。有重要的证据表明，暴露于As（III）与源自肝脏，肺，皮肤，膀胱，肾脏和前列腺的人类癌症有关。缺氧在肿瘤生长和侵袭性中起作用;对缺氧的适应至少在很大程度上由缺氧诱导因子-1 α（HIF-1α）介导。在本研究中，我们研究了As（III）对缺氧和常氧条件下的肝癌细胞系HepG 2中HIF-1α的影响。我们发现，在常氧条件下，As（III）可增加HIF-1α蛋白水平，而低氧介导的HIF-1 α诱导作用则降低。因此，As（III）对HIF-1α的作用依赖于两种转录调节，即通过NOX 4、PI 3 K/Akt和ERK 1/2介导的转录因子Nrf 2的转录调节以及通过调节HIF-1α蛋白的稳定性。与此一致，在内皮细胞的管形成试验中也观察到As（III）通过HIF-1α和Nrf 2参与的不同作用，其中Nrf 2和HIF-1α的敲低消除了As（III）的作用。总体而言，本研究表明，As（III）是一个有效的诱导HIF-1α在常氧下，但不是在缺氧下，这可能解释，部分，其致癌以及抗癌作用。常氧条件下，As（III）增加HIF-1α的表达，但降低其缺氧依赖性诱导表达。As（III）对HIF-1α的作用依赖于ROS、NOX 4、PI 3 K/Akt和ERK 1/2。常氧下的As（III）的影响涉及通过Nrf 2的转录调控。敲低Nrf 2和HIF-1α可消除As（III）在管形成试验中的作用。这些数据可以部分解释As（III）的致癌和抗癌作用。
Arsenite (As(III)) is widely distributed in nature and can be found in water, food, and air. There is significant evidence that exposure to As(III) is associated with human cancers originated from liver, lung, skin, bladder, kidney, and prostate. Hypoxia plays a role in tumor growth and aggressiveness; adaptation to it is, at least to a large extent, mediated by hypoxia-inducible factor-1α (HIF-1α). In the current study, we investigated As(III) effects on HIF-1α under normoxia and hypoxia in the hepatoma cell line HepG2. We found that As(III) increased HIF-1α protein levels under normoxia while the hypoxia-mediated induction of HIF1α was reduced. Thereby, the As(III) effects on HIF-1α were dependent on both, transcriptional regulation via the transcription factor Nrf2 mediated by NOX4, PI3K/Akt, and ERK1/2 as well as by modulation of HIF-1α protein stability. In line, the different effects of As(III) via participation of HIF-1α and Nrf2 were also seen in tube formation assays with endothelial cells where knockdown of Nrf2 and HIF-1α abolished As(III) effects. Overall, the present study shows that As(III) is a potent inducer of HIF-1α under normoxia but not under hypoxia which may explain, in part, its carcinogenic as well as anti-carcinogenic actions. As(III) increased HIF-1α under normoxia but reduced its hypoxia-dependent induction. The As(III) effects on HIF-1α were dependent on ROS, NOX4, PI3K/Akt, and ERK1/2. The As(III) effects under normoxia involved transcriptional regulation via Nrf2. Knockdown of Nrf2 and HIF-1α abolished As(III) effects in tube formation assays. The data may partially explain As(III)’s carcinogenic and anti-carcinogenic actions.
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影响因子：
4.5
作者：
Edwards, David H.;Li, Yiwen;Ellinsworth, David C.;Griffith, Tudor M.
通讯作者：
Griffith, Tudor M.
影响因子：
3.3
作者：
Diebold I;Petry A;Hess J;Görlach A
通讯作者：
Görlach A
影响因子：
6.6
作者：
Diebold, Isabel;Petry, Andreas;Goerlach, Agnes
通讯作者：
Goerlach, Agnes
影响因子：
11.4
作者：
Görlach A;Dimova EY;Petry A;Martínez-Ruiz A;Hernansanz-Agustín P;Rolo AP;Palmeira CM;Kietzmann T
通讯作者：
Kietzmann T
影响因子：
5.3
作者：
Fluegel, Daniela;Goerlach, Agnes;Kietzmann, Thomas
通讯作者：
Kietzmann, Thomas