Csiki Ildiko, Yanagisawa Kiyoshi, Haruki Nobuhiro, Nadaf Sorena, Morrow Jason D, Johnson David H, Carbone David P
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-6838, USA.
Cancer Res. 2006 Jan 1;66(1):143-50. doi: 10.1158/0008-5472.CAN-05-1357.
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-1alpha 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-1alpha to induce hypoxia-responsive genes under normoxic conditions. Our results identify two new mechanisms for regulation of COX-2 expression in NSCLC.
基因表达的缺氧诱导主要通过缺氧诱导因子-1（HIF-1）转录因子发生，是肿瘤生长中的关键步骤。环氧化酶-2（COX-2）在非小细胞肺癌（NSCLC）中通常过度表达。在本研究中，我们试图确定HIF-1在缺氧期间诱导COX-2表达中的作用。通过对缺氧反应基因的序列比较、COX-2启动子缺失分析和定点诱变，我们在COX-2启动子内鉴定出一个缺氧反应元件，该元件与HIF-1α相互作用，并构成肺癌细胞中COX-2缺氧激活机制的基础。非小细胞肺癌的蛋白质组学分析确定硫氧还蛋白-1是一种在非小细胞肺癌中过度表达且与预后不良相关的氧化还原蛋白。我们还表明，硫氧还蛋白-1在常氧条件下稳定HIF-1α以诱导缺氧反应基因。我们的结果确定了非小细胞肺癌中COX-2表达调控的两种新机制。
