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

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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
Volume284
Issue number15
DOIs
Publication statusPublished - Apr 10 2009
Externally publishedYes

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Aryl Hydrocarbon Receptor Nuclear Translocator
Hypoxia-Inducible Factor 1
Cyclooxygenase 2
Epidermal Growth Factor
Gene expression
Squamous Cell Carcinoma
Signal Transduction
Up-Regulation
Gene Expression
Tumors
Small Interfering RNA
Neoplasms
Growth
Epidermal Growth Factor Receptor
Uterine Cervical Neoplasms
Cell Movement
Epithelial Cells
Carcinogenesis
Proteins
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Epidermal growth factor-activated aryl hydrocarbon receptor nuclear translocator/HIF-1β signal pathway up-regulates cyclooxygenase-2 gene expression associated with squamous cell carcinoma. / Chang, Kwang Yu; Shen, Meng Ru; Lee, Mei Yi; Wang, Wen Lin; Su, Wu Chou; Chang, Wen Chang; Chen, Ben Kuen.

In: Journal of Biological Chemistry, Vol. 284, No. 15, 10.04.2009, p. 9908-9916.

Research output: Contribution to journalArticle

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abstract = "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.",
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