A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-κB promotes gastric tumour growth and angiogenesis.
A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-κB promotes gastric tumour growth and angiogenesis.
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DOI：
10.1038/sj.bjc.6606020
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发表时间：
2011-01-04
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
低氧诱导因子-1(HIF-1)在胃癌中的激活机制尚不清楚。鉴于核因子-κB(NF-κB)和缺氧诱导因子-1(HIF-1)在多种肿瘤血管生成中的作用，我们探讨了它们在胃癌中的关系。应用免疫组织化学方法检测2 5 1例胃癌组织中低氧诱导因子-1α和核转录因子κB/RELA的核表达。用含有超抑制性突变型IκBα(IκBαM)的逆转录病毒载体感染稳定的人胃癌细胞，进行动物实验和细胞培养实验。通过免疫组织化学、Western blotting、荧光素酶报告基因分析和半定量逆转录聚合酶链式反应，观察IκBαM对移植瘤血管生成和HIF 1α活性的影响。此外，还检测了NF-κB对HIF-1α降解和合成的影响。在临床胃癌标本中，缺氧诱导因子-1α的激活与RELA的激活呈正相关(P<；0.001)。IκBαM过表达抑制了移植瘤中的肿瘤生长、微血管密度和HIF-1α的激活。细胞培养实验表明，在低氧条件下，在翻译水平抑制低氧诱导的HIF-1α的表达可被抑制核因子-κB。低氧依赖的NF-κB/H IF-1/α通路的激活至少部分地通过促进血管生成促进了胃癌的发生。
The underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in gastric cancer remain unclear. As nuclear factor-κB (NF-κB) as well as HIF-1 have been implicated in angiogenesis of various cancers, we investigated their relationship in gastric cancer. Nuclear expressions of HIF-1α and NF-κB/RelA were assessed in 251 human gastric carcinoma specimens by immunohistochemical tissue array analysis. Stable human gastric cancer cells, infected with a retroviral vector containing super-suppressive mutant form of IκBα (IκBαM), were used for animal studies as well as cell culture experiments. Xenografted tumours were measured and IκBαM effects on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, western blotting, luciferase reporter assay, and semiquantitative reverse transcription–polymerase chain reaction. In addition, NF-κB effects on the HIF-1α degradation and synthesis were examined. Hypoxia-inducible factor-1α activation positively correlated with RelA activation in clinical gastric cancer samples (P<0.001). The IκBαM overexpression suppressed tumour growth, microvessel density, and HIF-1α activation in xenografted tumours. Cell culture experiments showed that hypoxia-induced HIF-1α expression was reduced by NF-κB inhibition under hypoxic conditions at the translational level. The hypoxia-dependent activation of the NF-κB/HIF-1α/VEGF pathway contributes, at least in part, to gastric cancer promotion via enhancement of angiogenesis.
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影响因子：
15.9
作者：
Baldwin, AS
通讯作者：
Baldwin, AS
影响因子：
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作者：
Lee, HS;Lee, HK;Kim, WH
通讯作者：
Kim, WH
影响因子：
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作者：
Mizokami, Ken;Kakeji, Yoshihiro;Maehara, Yoshihiko
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Maehara, Yoshihiko
影响因子：
10.5
作者：
Iyer, NV;Kotch, LE;Semenza, GL
通讯作者：
Semenza, GL
DOI：
10.1016/j.biocel.2004.08.012
发表时间：
2005-03-01
影响因子：
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作者：
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通讯作者：
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