S100A8 and S100A9, two heterodimer-forming members of the cytosolic S100 Ca(2+) signaling
protein family, are overexpressed in various
cancer types, including
prostate cancer. They act as proinflammatory danger signals when secreted to the extracellular space and are thought to play an important role during
tumorigenesis, affecting inflammatory processes, proliferation, invasion and
metastasis of
tumor cells. Despite this fact, little is known about
tumor environmental factors influencing S100A8/A9 expression. The aim of this study was to test the effect of
hypoxia and its master transcriptional regulator
hypoxia-inducible factor 1 (HIF-1) on S100A8/A9 expression.
Hypoxia treatment resulted in induction of S100A8/A9
protein and
mRNA expression in prostate epithelial BPH-1 cells, the latter was also confirmed in the
prostate cancer cell lines PC-3 and DU-145. Furthermore, overexpression of HIF-1α caused increase in S100A8/A9
protein and
mRNA expression as well as secretion. Functional
hypoxia response elements mediating promoter activation on HIF-1α overexpression were identified within the S100A8 and S100A9 promoters using promoter
luciferase reporter constructs. Binding of HIF-1α to S100A8 and S100A9 promoters was confirmed by
chromatin immunoprecipitation. Immunohistochemical analysis of a
prostate cancer tissue array showed clear correlation of S100A8 and S100A9 with HIF-1α expression. Multivariate proportional hazard analysis revealed association of high S100A9 level with time to
prostate cancer recurrence. In conclusion, we identified
hypoxia and HIF-1 as novel regulators of S100A8/A9 expression in
prostate cancer. S100A9 might be useful as prognostic marker for
prostate cancer recurrence after radical
prostatectomy.