The Differential Effect of Egf on the Induction of Cyclooxygenase-2 Expression in Squamous and Adenocarcinoma Cells

Project: A - Government Institutionb - Ministry of Science and Technology

Description

It is well documented that cyclooxygenase-2 (COX-2) expression contributes to increased antiapoptotic, proangiogenic, and metastatic potential in cancer cells, and COX-2 deregulation is correlated with tumor progression. COX-2 derived PGE2 stimulates angiogenesis via the hypoxia-inducible factor-1α (HIF-1α) leading to the induction of VEGF. In studying the transcriptional regulation of human COX-2 gene, we previously found that c-Jun induction plays a crucial role in EGF-induced gene expression of COX-2. We also found that overexpression of c-Jun N-terminal phosphorylation site mutants induces similar stimulatory effects on COX-2 promoter activity and protein expression as c-Jun wild type. In addition, TAM-67, a mutant of c-Jun that lacks the N-terminal transactivation domain of c-Jun, also enhances COX-2 expression in cells treated with EGF. These results indicate that c-Jun N-terminal phosphorylation is not required for EGF-induced expression of COX-2. c-Jun might also recruit other transcription factors to coactivate COX-2 expression. Thus, we want to further identify what factors could be as coactivators to regulate c-Jun-mediated gene expression. Interestingly, in our recent work, we found that aryl hydrocarbon receptor nuclear translocator (ARNT) interacted with c-Jun to activate gene transcription of COX-2. Although c-Jun could be induced by EGF in all cell lines, our preliminary data showed that EGF induced COX-2 expression in most types of squamous cell but not in adenocarcinoma cell. Thus, we raise the hypothesis that EGF could not induce and activate the formation of c-Jun/ARNT complex or other c-Jun/X complex in adenocarcinoma cell, resulting in failure to regulate COX-2 expression. The other possibility to excuse the phenomenon observed in adenocarcinoma cell is that existing repressors could inhibit the effect of EGF on the induction of COX-2 expression. In the present three-year proposal, we will study the mechanisms involved in the differential effect of EGF on the induction of COX-2 expression in squamous and adenocarcinoma cells. Three specific aims are proposed as follows: 1. To study the mechanisms involved in the regulation of EGF-induced interaction between c-Jun and ARNT. 2. To identify the factors involved in the differential effect of EGF on the COX-2 expression in squamous cell and adenocarcinoma cell 3. To study the correlation among EGFR, COX-2 expression and c-Jun/ARNT or other factors in cancer tissues In this study, we will reveal the mechanisms responsible for the differential expression of COX-2 in different cell types, and also raise the hypothesis that ARNT/c-Jun complex in squamous cell or the presence of inhibitors in adenocarcinoma could be a pivotal factor in the regulation of COX-2 expression. Thus, identification of these factors will further provide a new target for the usage of cancer therapeutics.
StatusFinished
Effective start/end date8/1/117/31/12

Keywords

  • ARNT
  • cyclooxygenase-2
  • c-Jun
  • EGF
  • cell growth
  • gene regulation