Abstract
Hypoxic induction of gene expression occurs mainly via the hypoxia-inducible factor-1 (HIP-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-1α 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-1α to induce hypoxia-responsive genes under normoxic conditions. Our results identify two new mechanisms for regulation of COX-2 expression in NSCLC.
Original language | English (US) |
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Pages (from-to) | 143-150 |
Number of pages | 8 |
Journal | Cancer research |
Volume | 66 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2006 |
ASJC Scopus subject areas
- Oncology
- Cancer Research