Epidermal growth factor-activated aryl hydrocarbon receptor nuclear translocator/HIF-1{beta} signal pathway up-regulates cyclooxygenase-2 gene expression associated with squamous cell carcinoma.
Hypoxia-inducible factor (HIF) accumulates when tumors grow under hypoxic conditions. The genesis of tumors, however, usually involves normoxic conditions. In this study, we were interested in examining the potential role of aryl hydrocarbon receptor nuclear translocator (ARNT)/HIF-1beta in tumor growth under normoxic conditions, specifically when cells are treated with epidermal growth factor (EGF), which is known to affect the gene expression of tumor growth-related protein COX-2 (cyclooxygenase-2). The results showed that EGF receptor inhibitor, AG1478, abolished EGF-induced nuclear accumulation of ARNT as well as the expression of COX-2. ARNT small interfering RNA inhibited the promoter activity, mRNA level, and protein expression of COX-2 in cells treated with EGF. In contrast, CoCl(2)-induced HIF-1alpha exhibited no effect on COX-2 expression. EGF also stimulated the formation of the ARNT.c-Jun complex as well as the complex binding to the COX-2 promoter. ARNT small interfering RNAs blocked EGF-activated cell migration. Moreover, COX-2 and ARNT were cohorts present distinctively in clinical specimens of human cervical squamous cell carcinoma and were almost nondetectable in adjacent normal or noncancerous cervical tissues. Our results revealed that ARNT plays an important role in EGF-regulated COX-2 gene expression and may thus be related to either a cause or a consequence of tumorigenesis in cervical cancer.
Chang
Kwang-Yu
KY
National Institute of Cancer Research, National Health Research Institutes, Tainan 701, Taiwan.
Shen
Meng-Ru
MR
Lee
Mei-Yi
MY
Wang
Wen-Lin
WL
Su
Wu-Chou
WC
Chang
Wen-Chang
WC
Chen
Ben-Kuen
BK
D021581:Active Transport, Cell Nucleus; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011799:Quinazolines; D012333:RNA, Messenger / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism
D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C101044:RTKI cpd; D003035:Cobalt; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; C018021:cobaltous chloride