Cooperation between transcription factor AP-1 and NF-kappaB in the induction of interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia.
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-kappaB binding sites were necessary for IL-8 induction by hypoxia. Consistently, hypoxia induced both AP-1 and NF-kappaB activity. These data suggest that hypoxic environments upregulate the IL-8 gene via cooperation of NF-kappaB and AP-1 and contribute to the progression and metastasis of human pancreatic cancer.
Shi
Q
Q
Department of Gastrointestinal Oncology and Digestive Diseases, The University of Texas M.D. Anderson Cancer Center, Houston 77030. USA.
Le
X
X
Abbruzzese
J L
JL
Wang
B
B
Mujaida
N
N
Matsushima
K
K
Huang
S
S
Xiong
Q
Q
Xie
K
K
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D015687:Cell Hypoxia / Q000235:genetics* / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
D017931:DNA Primers; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018808:Transcription Factor AP-1