Thioredoxin-1 modulates transcription of cyclooxygenase-2 via hypoxia-inducible factor-1α in non-small cell lung cancer
Thioredoxin-1 modulates transcription of cyclooxygenase-2 via hypoxia-inducible factor-1α in non-small cell lung cancer
复制标题
DOI：
10.1158/0008-5472.can-05-1357
复制
发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Carbone, DP
中科院分区：
文献类型：
--
作者：
Csiki, I;Yanagisawa, K;Carbone, DP
低氧诱导基因表达主要通过低氧诱导因子-1(HIF-1)转录因子进行，是肿瘤生长的关键步骤。环氧合酶-2(COX-2)在非小细胞肺癌(NSCLC)中普遍过表达。在这项研究中，我们试图确定HIF-1在低氧诱导COX-2表达中的作用。通过低氧反应基因序列比较、COX-2启动子缺失分析和定点突变，我们在COX-2启动子中发现了一个与HIF-1α相互作用的低氧反应元件，它是肺癌细胞低氧激活COX-2的基础。NSCLC的蛋白质组学分析证实硫氧还蛋白-1是一种在NSCLC中高表达的氧化还原蛋白，与预后不良相关。我们还表明，硫氧还蛋白-1稳定HIF-1α，在常氧条件下诱导低氧反应基因。我们的结果确定了两种新的机制来调节非小细胞肺癌中COX-2的表达。
Hypoxic induction of gene expression occurs mainly via the hypoxia-inducible factor-1 (HIF-1) transcription factor and is a critical step in tumor growth. Cyclooxygenase-2 (COX-2) is commonly overexpressed in non-small cell lung cancer (NSCLC). In this study, we sought to determine the role of HIF-1 in the induction of COX-2 expression during hypoxia. Through sequence comparison of hypoxia-responsive genes, COX-2 promoter deletion analysis, and site-directed mutagenesis, we identified a hypoxia-responsive element within the COX-2 promoter that interacts with HIF-1 alpha and underlies the mechanism of hypoxic activation of COX-2 in lung cancer cells. Proteomic analysis of NSCLC identified thioredoxin-1 as a redox protein overexpressed in NSCLC correlated with poor prognosis. We also show that thioredoxin-1 stabilizes HIF-1 alpha to induce hypoxia-responsive genes under normoxic conditions. Our results identify two new mechanisms for regulation of COX-2 expression in NSCLC.