Journal
CANCER RESEARCH
Volume 66, Issue 1, Pages 143-150Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-05-1357
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Funding
- NCI NIH HHS [K24CA080908, CA90949, CA77839, CA68485, CA076321] Funding Source: Medline
- NCRR NIH HHS [RR00095] Funding Source: Medline
- NIDDK NIH HHS [DK48831] Funding Source: Medline
- NIGMS NIH HHS [GM15431] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [K24CA080908, P30CA068485, P01CA077839, R01CA076321, P50CA090949] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK048831] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P50GM015431, P01GM015431] Funding Source: NIH RePORTER
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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.
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