Hypoxia-Inducible Factor-2α Correlates to Distant Recurrence and Poor Outcome in Invasive Breast Cancer
Hypoxia-Inducible Factor-2α Correlates to Distant Recurrence and Poor Outcome in Invasive Breast Cancer
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DOI：
10.1158/0008-5472.can-08-1135
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Jirstrom, Karin
中科院分区：
文献类型：
--
作者：
Helczynska, Karolina;Larsson, Anna-Maria;Jirstrom, Karin
已经提出了两种低氧诱导因子（HIF）-α亚基HIF-1 α和HIF-2 α在各种肿瘤和细胞系中的差异调节以及靶基因特异性。在乳腺癌中，HIF-1 α的预后意义尚不明确，HIF-2 α的预后意义在很大程度上尚不清楚。通过对512例浸润性乳腺癌患者组织芯片中HIF-1 α、HIF-2 α和血管内皮生长因子（VEGF）表达的免疫组化分析，我们研究了2种HIF-α亚基的表达模式与确定的临床病理变量、VEGF表达和生存率的关系。在第二组179例患者中，还分析了HIF-1 α和HIF-2 α蛋白水平及其对生存率的影响。为了评估每个亚基在低氧应答和VEGF诱导中的单独作用，在低氧诱导和/或通过siRNA敲低HIF-α亚基后，通过Western印迹和定量实时PCR技术在培养的乳腺癌细胞中进一步研究HIF-α蛋白和HIF-α和VEGF mRNA水平。我们发现，尽管乳腺癌标本中HIF-1 α和HIF-2 α蛋白水平不相关，但HIF-1 α和HIF-2 α的高水平与VEGF的高表达相关。HIF-2 α表达是一个独立的预后因素，与减少无复发和乳腺癌特异性生存相关，而HIF-1 α没有表现出这些相关性。在培养的细胞中，急性缺氧诱导HIF-蛋白。在长期缺氧，HIF-2 α仍然积累，而HIF-1 α蛋白水平下降，在协议的氧水平和时间依赖性诱导HIF最近报道的神经母细胞瘤。[Cancer Res 2008;68（22）：9212-20]
Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1 alpha and HIF-2 alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1 alpha is not clear-cut and that of HIF-2 alpha is largely unknown. Using IHC analyses of HIF-1 alpha, HIF-2 alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1 alpha and HIF-2 alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1 alpha and HIF-2 alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1 alpha and HIF-2 alpha associated to high VEGF expression. HIF-2 alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1 alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2 alpha remained accumulated, whereas HIF-1 alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma. [Cancer Res 2008;68(22):9212-20]