Cooperation Between Transcription Factor AP-1 and NF-kappa B in the Induction of Interleukin-8 in Human Pancreatic Adenocarcinoma Cells by Hypoxia

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Abstract
The expression of interleukin-8 (IL-8) has been shown to play an important role in the growth and metastasis of human pancreatic cancer. In the present study, we investigated the regulation of IL-8 gene expression by hypoxic environments. Exposure of the human pancreatic cancer cells COLO357 and FG to hypoxia in culture resulted in a time-dependent increase in steady-state levels of IL-8 mRNA and IL-8 protein secretion. The induction of IL-8 expression was correlated with transcriptional activation of the IL-8 gene. Deletion and point mutation analyses of the IL-8 promoter revealed that both AP-1 and NF-kappa B binding sites were necessary for IL-8 induction by hypoxia. Consistently, hypoxia induced both AP-1 and NF-kappa B activity. These data suggest that hypoxic environments upregulate the IL-8 gene via cooperation of NF-kappa B and AP-1 and contribute to the progression and metastasis of human pancreatic cancer.