The incidence of distant
metastases is higher in the tumours with low
oxygen pressure than in those with high
oxygen pressure. It is well known that
hypoxia induces the transcription of various genes involved in angiogenesis and anaerobic metabolism necessary for the growth of tumour cells in vivo, suggesting that
hypoxia may also induce the transcription of
metastasis-associated genes. We sought to identify the
metastasis-associated genes differentially expressed in tumour cells under hypoxic conditions with the use of
a DNA microarray system. We found that
hypoxia enhanced the expression of
autocrine motility factor mRNA in various
cancer cells and also enhanced the random motility of
pancreatic cancer cells.
Autocrine motility factor inhibitors abrogated the increase of motility under hypoxic conditions. In order to explore the roles of
hypoxia-inducible factor-1alpha, we established
hypoxia-inducible factor-1alpha-transfectants and dominant negative
hypoxia-inducible factor-1alpha-transfectants. Transfection with
hypoxia-inducible factor-1alpha and dominant-negative
hypoxia-inducible factor-1alpha enhanced and suppressed the expression of
autocrine motility factor/phosphohexase
isomerase/
neuroleukin mRNA and the random motility, respectively. These results suggest that
hypoxia may promote the metastatic potential of
cancer cells through the enhanced
autocrine motility factor/phosphohexase
isomerase/
neuroleukin mRNA expression and that the disruption of the
hypoxia-inducible factor-1 pathway may be an effective treatment for
metastasis.