Epidermal growth factor-activated aryl hydrocarbon receptor nuclear translocator/HIF-1β signal pathway up-regulates cyclooxygenase-2 gene expression associated with squamous cell carcinoma

Kwang Yu Chang, Meng Ru Shen, Mei Yi Lee, Wen Lin Wang, Wu Chou Su, Wen Chang Chang, Ben Kuen Chen

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20 Citations (Scopus)


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-1β 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, CoCl2-induced HIF-1α exhibited no effect on COX-2 expression. EGF also stimulated the formation of theARNT·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-2gene expression andmaythus be related to either a cause or a consequence of tumorigenesis in cervical cancer.

Original languageEnglish
Pages (from-to)9908-9916
Number of pages9
JournalJournal of Biological Chemistry
Issue number15
Publication statusPublished - Apr 10 2009
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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